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Wang Z, Li Y, Wang X, Zhang W, Chen Y, Lu X, Jin C, Tu L, Jiang T, Yang Y, Ma X, Zeng J, Wen Y, Efferth T. Precision Strike Strategy for Liver Diseases Trilogy with Xiao-Chai-Hu Decoction: A Meta-Analysis with Machine Learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156796. [PMID: 40347886 DOI: 10.1016/j.phymed.2025.156796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/30/2025] [Accepted: 04/20/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND AND PURPOSE The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques. METHODS Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected. RESULTS XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC. CONCLUSION XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.
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Affiliation(s)
- Zexin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaobao Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaohua Lu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Chunmei Jin
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Lang Tu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiqin Yang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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Mlawer SJ, Pinto FR, Sikes KJ, Connizzo BK. Coordination of Glucose and Glutamine Metabolism in Tendon Is Lost in Aging. J Orthop Res 2025. [PMID: 40384411 DOI: 10.1002/jor.26100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/20/2025]
Abstract
Tendinopathy is a chronic, degenerative disease that has increased prevalence in aged populations, and is characterized by a loss in extracellular matrix (ECM) integrity. Recent work has clearly demonstrated age-related deficits in ECM synthesis with aging, as well as some changes to metabolic activity. Since glucose metabolism is critical to protein synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We used our previously developed flexor tendon explant model to expose young and aged tendon explants to various concentrations of glucose and glutamine supplementation and observe changes in metabolic activity, matrix composition, matrix biosynthesis, and expression of metabolic and ECM genes. We hypothesized that elevated levels of glucose and glutamine would lead to increased ECM remodeling as well as elevated gene expression of their respective pathways in young tendons, with no such effect in aged tendons. Interestingly, we found that glutamine processing is affected by glucose levels with increased expression of key glutamine processing pathways with increased glucose, but this effect was lost with aging. We also observed that ECM remodeling is directly related to both glucose and glutamine processing with altered glycosaminoglycan and collagen synthesis with glucose and glutamine media concentration. Overall, our work reveals that glucose and glutamine are intricately linked for both tenocyte health and ECM homeostasis and that their metabolism could be one of the key drivers of age-related deficiencies in tissue maintenance.
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Affiliation(s)
- Samuel J Mlawer
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA
| | - Felicia R Pinto
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA
| | - Katie J Sikes
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Brianne K Connizzo
- Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA
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Gao Z, Yang Z, Luo M, Pei Z, Xu W, Liu Y, Guo J, Xiang X, Yu Z, Zhao S, Guan J. Trienzyme-in-One Nanoparticle Making Multifunctional Synergistic Nanorobot for Tumor Therapy. SMALL METHODS 2025:e2500142. [PMID: 40351003 DOI: 10.1002/smtd.202500142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/28/2025] [Indexed: 05/14/2025]
Abstract
Current nanoparticle-based drug delivery systems for tumor therapy face significant challenges in intratumoral penetration and cellular internalization, leading to poor therapeutic efficacy. Herein, it is demonstrated that the sequential integration of glucose oxidase (GOx), catalase (CAT), and urease (URE) onto the half surface of biotin-modified Janus nanoparticles via the chemical coupling way produces nanorobots of multifunctionality and synergistic effect (denoted as UCGPJNRs). They can autonomously and powerfully move in tumor microenvironment (TME) by using endogenous urea as a fuel, enabling to penetrate deeper than 0.55 mm into tumor tissues, ≈5.5-fold of the previous counterparts. The UCGPJNRs perform motion-enhanced biotin receptor-mediated endocytosis and endoplasmic reticulum/Golgi apparatus pathway-mediated exocytosis, greatly improving the internalization efficiency of tumor cells. They release NH3 when moving to produce selective toxicity against tumor cells in hypoxic TME. Further, they enhance the glucose consumption by ≈three times due to the motion-accelerated GOx/CAT cascade reaction, disrupting the metabolism against tumor cells on a large area. After intratumorally injecting into tumor-bearing mice, UCGPJNRs can significantly amplify the in vivo tumor growth inhibition rate through their synergistic effect. This work provides a plausible strategy to overcome current limitations in tumor treatment by anchoring multiple bioenzymes on one nanoparticle.
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Affiliation(s)
- Zhixue Gao
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Zili Yang
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Ming Luo
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Ziye Pei
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Wentao Xu
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Yushan Liu
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Jie Guo
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Xia Xiang
- Oil Crops Research Institute of Chinese Academy of Agricultural Sciences, Oil Crops and Lipids Process Technology National & Local Joint Engineering Laboratory, Wuhan, 430062, China
| | - Zili Yu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Suling Zhao
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
| | - Jianguo Guan
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China
- Research Center for Optoelectromagnetic Functional Materials Technology, Wuhan Institute of Photochemistry and Technology, 7 North Bingang Road, Wuhan, 430083, China
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Li Y, Shi M, Bie B, Tian H, Li J, Li Z, Sun J. NRF1-Induced lncRNA DDX11-AS1 Contributes to the Progression of Hepatocellular Carcinoma via Activating CA9 Expression and the MEK/ERK Pathway. J Hepatocell Carcinoma 2025; 12:891-908. [PMID: 40356690 PMCID: PMC12067462 DOI: 10.2147/jhc.s516656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Purpose DDX11 antisense RNA 1 (DDX11-AS1) has been recognized for its strong correlation with hepatocellular carcinoma (HCC). Nevertheless, the exact biological functions and fundamental molecular processes of DDX11-AS1 in HCC require further in-depth investigation. Methods A comprehensive bioinformatics analysis was carried out to explore the expression of DDX11-AS1 and its clinical implication in HCC utilizing the TCGA data. qRT-PCR was employed to validate the expression of DDX11-AS1 in HCC tissues/cell lines. RNA fluorescence in situ hybridization (RNA-FISH) was used to observe the subcellular localization of DDX11-AS1 in HCC cells. Loss-of-function experiments, both in vitro and in vivo, were executed to elucidate the biological functions of DDX11-AS1 in HCC. RNA sequencing (RNA-seq) was employed to identify genes and signaling pathways potentially regulated by DDX11-AS1. Rescue experiments were conducted to validate that carbonic anhydrase IX (CA9) mediates DDX11-AS1 promoting HCC progression. The influence of nuclear respiratory factor 1 (NRF1) on the transcription of DDX11-AS1 was investigated through dual-luciferase reporter assays and ChIP-qPCR. Results The increased expression of DDX11-AS1 is positively associated with several aggressive clinical characteristics (pathologic T stage, histologic grade, AFP level, and vascular invasion), and is closely linked to unfavorable outcomes in HCC patients, acting as a separate hazardous factor for overall survival. DDX11-AS1 is predominantly situated in the nucleus of HCC cells. DDX11-AS1 knockdown impeded the growth, migration, and invasion capabilities of HCC cells in vitro, and reduced the tumor enlargement in a subcutaneous mouse model. RNA-Seq unveiled that silencing DDX11-AS1 lessened the expression of CA9 and suppressed the activity of the MEK/ERK signaling cascade in HCC cells. Rescue experiments uncovered that CA9 acts as a downstream target facilitating the cancer-causing roles of DDX11-AS1 in HCC. Furthermore, DDX11-AS1 was revealed to be transcriptionally regulated by NRF1. Conclusion DDX11-AS1, a NRF1-induced lncRNA, facilitates HCC development by upregulating CA9 expression and activating the MEK/ERK signaling cascade.
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Affiliation(s)
- Yingnan Li
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Center for Tumor and Immunology, The Precision Medical Institute, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710115, People’s Republic of China
| | - Mengjiao Shi
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
| | - Beibei Bie
- Department of Pharmacy, Medical School, Xi’an Peihua University, Xi’an, 710125, People’s Republic of China
| | - Hongwei Tian
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
| | - Jun Li
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
| | - Zongfang Li
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Center for Tumor and Immunology, The Precision Medical Institute, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710115, People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
| | - Jin Sun
- Department of General Surgery, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China
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Long X, Liu R, Zhang M, Wu Y, Zhang S, Tang K, Wang H. Integrated proteomics and phosphoproteomics study reveals the potential tumour suppressive function of PCK2 in hepatocellular carcinoma. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:3526-3537. [PMID: 40235441 DOI: 10.1039/d5ay00090d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. Patients are often diagnosed at advanced stages and have short overall survivals. Thus, there is an urgent need to understand the underlying mechanism of HCC development and discover new drug targets. In the present study, an ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based approach was used to investigate the proteome and phosphoproteome alterations between tumour and non-tumour tissues of HCC patients. In total, 678 proteins and 350 phosphoproteins were significantly changed between the two groups. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that glycolysis/glucogenesis was one of the most significantly enriched pathways of down-regulated phosphoproteins and PCK2 was one hub protein in this pathway. Furthermore, the phosphosite of the Ser304 residue in PCK2 is highly evolutionarily conserved among different species and is located near to the GDP, Mn2+ binding sites and kinase activity site, which indicate that the phosphorylation of Ser304 may regulate PCK2 activity. HepG2 cell proliferation, invasion and migration were significantly increased when treated with 3-mercaptopicolinic acid, an inhibitor of PCK2, which demonstrated the tumour suppressive activity of PCK2 in HCC. In addition, the low mRNA expression of PCK2 was correlated with poor overall survival of live cancer patients. Overall, our proteomic and phosphoproteomic study revealed the tumour suppressive function of PCK2 in HCC and indicated that activation of its expression or activity may be a potential therapeutic strategy for HCC treatment.
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Affiliation(s)
- Xiao Long
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
| | - Rong Liu
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
| | - Meng Zhang
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
| | - Yannan Wu
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
| | - Shun Zhang
- Guoke Ningbo Life Science and Health Industry Research Institute, No. 159 Beijiao Road, Ningbo City, Zhejiang Province, China.
| | - Keqi Tang
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
| | - Hongxia Wang
- Institute of Mass Spectrometry, Zhejiang Engineering Research Center of Advanced Mass spectrometry and Clinical Application, School of Material Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
- Zhenhai Institute of Mass Spectrometry, Ningbo 315211, China
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Chen X, Zheng J, Wang C, Teng M, Jiang J, Wu F. Exposure of Parental Zebrafish to Difenoconazole throughout Their Life Cycle May Lead to Developmental Toxicity in the F1 Generation through Epigenetic Changes in Gametes, Impaired Nutrient Supply from the Ovum, and Maternal Transfer of Difenoconazole. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:6477-6487. [PMID: 40153714 DOI: 10.1021/acs.est.4c13073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/30/2025]
Abstract
Difenoconazole is a widely used agricultural fungicide that has been frequently detected in aquatic environments. Given its stable presence in aquatic environments, long-term exposure of wild fish may pose a risk to offspring embryonic development. This study demonstrated that exposure of zebrafish to environmental concentrations of difenoconazole throughout their life cycle resulted in abnormal development of offspring embryos/larvae, including decreased heart rate, delayed hatching, increased malformation rate, shortened body length, and increased mortality. These changes were significantly correlated with the affected apoptosis, autophagy, energy metabolism and MAPK signaling pathways in F1 generation. This transgenerational toxic effect results from epigenetic alterations in gametes, impaired nutrient supply from the ovum, and maternal transfer of difenoconazole. After exposure to difenoconazole, the development of female fish offspring was affected more than that of male fish offspring, which was mainly caused by the impaired nutrient supply from the ovum and the maternal transfer of difenoconazole. Because this transgenerational developmental toxicity was observed at environmental levels, difenoconazole may pose a threat to the survival of wild larvae and therefore a risk to wild fish populations.
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Affiliation(s)
- Xiangguang Chen
- National-Regional Joint Engineering Research Center for Soil Pollution Control and Remediation in South China, Guangdong Key Laboratory of Integrated Agro-environmental Pollution Control and Management, Institute of Eco-environmental and Soil Sciences, Guangdong Academy of Sciences, Guangzhou 510650, China
| | - Junyue Zheng
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Sciences, China Agricultural University, Beijing 100193, China
| | - Chengju Wang
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Sciences, China Agricultural University, Beijing 100193, China
| | - Miaomiao Teng
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Jiazhen Jiang
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Sciences, China Agricultural University, Beijing 100193, China
| | - Fengchang Wu
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
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Ji G, Feng X, Hu C, Zhang J, Sheng H, Na R, Li F, Wang Y, Ma Y, Cai B, Ma Y. HADHA promotes apoptosis and inflammatory response in bovine endometrial epithelial cells by regulating transcription and metabolism. Int J Biol Macromol 2025; 304:140980. [PMID: 39952496 DOI: 10.1016/j.ijbiomac.2025.140980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/23/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Endometritis in dairy cows significantly impacts their reproductive performance. However, its underlying mechanisms remain unclear. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit-alpha (HADHA) is known to regulate the occurrence of various diseases, but its role in bovine endometritis is poorly understood. In the present study, an in vitro bovine endometrial epithelial cells (BEECs) inflammation model was constructed to explore the effects of HADHA on inflammation, proliferation, and apoptosis. Functional analyses based on HADHA interference and overexpression revealed that it positively regulated the expression of IL-6, IL-8, and IL-1β in lipopolysaccharide (LPS)-induced BEECs, enhancing reactive oxygen species (ROS) production and promoting inflammation. Concurrently, HADHA decreased the expression of PCNA, CDK2, and CDK4, inhibited mitotic transition of BEECs from S to G2 phase, and negatively regulated BEEC proliferation. It also increased BAX and Caspase-3 expression while decreasing BCL2 expression, hence promoting BEECs apoptosis. Transcriptomic and metabolomic analyses indicated that HADHA modulated inflammation in BEECs by affecting pathways such as the TGF-beta signaling pathway, fatty acid metabolism, and p53 signaling. These findings provide novel insights into HADHA's role in bovine endometritis and reveal future research directions on its regulatory mechanisms.
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Affiliation(s)
- Guoshang Ji
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Xue Feng
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Chunli Hu
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Junxing Zhang
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Hui Sheng
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Tianjin Key Laboratory of Animal Molecular Breeding and Biotechnology, Tianjin Engineering Research Center of Animal Healthy Farming, Institute of Animal Science and Veterinary, Tianjin Academy of Agricultural Sciences, Tianjin 300381,China
| | - Rina Na
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Fen Li
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Yachun Wang
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, MARA, National Engineering Laboratory of Animal Breeding, State Key Laboratory of Farm Animal Biotech Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Yanfen Ma
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Bei Cai
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China
| | - Yun Ma
- Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China.
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Li H, Hu X, Wang L, Gu X, Chen S, Tang Y, Chen Y, Chen J, Yuan Z, Wang Y. The Expression of Ferroptosis-Related Genes in Hepatocellular Carcinoma and Their Relationships With Prognosis. J Hepatocell Carcinoma 2025; 12:629-648. [PMID: 40130081 PMCID: PMC11932120 DOI: 10.2147/jhc.s500394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/05/2025] [Indexed: 03/26/2025] Open
Abstract
Background Ferroptosis, a form of cell death discovered in recent years, is expected to provide new targets for the diagnosis and treatment of hepatocellular carcinoma (HCC) through further research. Methods Based on data from The Cancer Genome Atlas (TCGA), we screened HCC-associated genes from 259 candidate genes in the FerrDb database. The screened genes were subjected to differential expression analysis, survival analysis, correlation analysis with clinical data, and univariate and multivariate Cox regression analysis. The results were validated with the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database and the Human Protein Atlas (HPA) database, and signaling pathways were analyzed with the Gene Set Enrichment Analysis (GSEA) enrichment analysis. Human normal hepatocytes and different liver cancer cell lines were used to verify the expression levels of genes, using quantitative reverse transcription PCR (RT-qPCR). Results Eight ferroptosis-related genes were finally selected, including ACSL3, ASNS, CHMP5, MYB, PCK2, PGD, SLC38A1, and YY1AP1. The expression of eight genes except PCK2 was significantly correlated with a lower survival rate of HCC, and the expression of PCK2 showed a correlation with a higher survival rate of HCC. The expression of all eight genes was also correlated with clinical traits. GSEA enrichment analysis obtained many pathways such as apoptosis, endocytosis, pathways in cancer, Wnt signaling pathway, primary bile acid biosynthesis, and fatty acid metabolism pathway. Conclusion The ACSL3, ASNS, CHMP5, MYB, PCK2, PGD, SLC38A1, and YY1AP1 genes may become markers and new targets for early diagnosis and prognostic assessment of HCC.
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Affiliation(s)
- Hongxu Li
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Xinyue Hu
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Li Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xiangran Gu
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Shibin Chen
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Yixuan Tang
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Yuan Chen
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Jin Chen
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Zhengrong Yuan
- College of Biological Sciences and Technology, Beijing Forestry University, Beijing, People’s Republic of China
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
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Zhou D, Li X, Liu W, Zhang M, Cheng Y, Xu Z, Gao J, Wang Y. A novel approach for engineering DHCM/GelMA microgels: application in hepatocellular carcinoma cell encapsulation and chemoresistance research. Front Bioeng Biotechnol 2025; 13:1564543. [PMID: 40161518 PMCID: PMC11949893 DOI: 10.3389/fbioe.2025.1564543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Liver cancer, a highly aggressive malignancy, continues to present significant challenges in therapeutic management due to its pronounced chemoresistance. This resistance, which undermines the efficacy of conventional chemotherapy and targeted therapies, is driven by multifaceted mechanisms, with increasing emphasis placed on the protective role of the tumor microenvironment (TME). The hepatocellular carcinoma extracellular matrix (ECM), a primary non-cellular component of the TME, has emerged as a critical regulator in cancer progression and drug resistance, particularly in hepatocellular carcinoma cell (HCC). In this study, a hybrid biomimetic hydrogel was engineered by integrating decellularized hepatocellular carcinoma matrix (DHCM) with gelatin methacrylate (GelMA) precursors. This composite DHCM/GelMA hydrogel was designed to replicate the physicochemical and functional properties of the hepatocellular carcinoma ECM, thereby offering a biomimetic platform to explore the interactions between HCCs and their microenvironment. Leveraging a custom-designed microfluidic 3D printing platform, we achieved high-throughput fabrication of HCC-encapsulated DHCM/GelMA microgels, characterized by enhanced uniformity, biocompatibility, and scalability. These microgels facilitated the construction of hepatocellular carcinoma microtissues, which were subsequently employed for chemoresistance studies. Our findings revealed that DHCM/GelMA microgels closely mimic the hepatocellular carcinoma tumor microenvironment, effectively recapitulating key features of ECM-mediated drug resistance. Mechanistic studies further demonstrated that DHCM significantly upregulates the expression of Aquaporin 3 (AQP3) in the encapsulated HCCs. This upregulation potentially activates mTOR signaling-associated autophagy pathways, thereby enhancing chemoresistance in HCCs. These biomimetic models provide a robust and versatile platform for studying the underlying mechanisms of drug resistance and evaluating therapeutic interventions. This innovative approach highlights the potential of DHCM/GelMA microgels as a transformative tool in cancer-associated tissue engineering and anticancer drug screening. By enabling detailed investigations into the role of ECM in chemoresistance, this study contributes to advancing therapeutic research and offers promising strategies to overcome drug resistance, ultimately improving clinical outcomes in liver cancer treatment.
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Affiliation(s)
- Dandan Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Geriatric Medicine, Jiulongpo People’s Hospital of Chongqing, Chongqing, China
| | - Xiaoxiao Li
- Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Tissue Repairing and Biotechnology Research Center, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wencun Liu
- Department of Radiology, Jiulongpo People’s Hospital of Chongqing, Chongqing, China
| | - Mingjun Zhang
- Department of Clinical Laboratory, Jiulongpo People’s Hospital of Chongqing, Chongqing, China
| | - Ying Cheng
- Department of Clinical Laboratory, Jiulongpo People’s Hospital of Chongqing, Chongqing, China
| | - Zhousong Xu
- Department of Clinical Laboratory, Jiulongpo People’s Hospital of Chongqing, Chongqing, China
| | - Jian Gao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yiyang Wang
- Department of Orthopedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Tissue Repairing and Biotechnology Research Center, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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10
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Xu R, Li J, Zhu J, Guo F, Zhang C, Chen K, Xu J. Suppression of PCK1 attenuates neuronal injury and improves post-resuscitation outcomes. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167674. [PMID: 39826848 DOI: 10.1016/j.bbadis.2025.167674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 01/12/2025] [Accepted: 01/12/2025] [Indexed: 01/22/2025]
Abstract
Cardiac arrest (CA) is a critical medical emergency that can occur in both patients with preexisting conditions and otherwise healthy individuals. Despite successful resuscitation through cardiopulmonary resuscitation (CPR), many survivors are at significant risk of developing post-cardiac arrest syndrome (PCAS), a complex systemic response to CA that includes brain injury as a major component. Phosphoenolpyruvate carboxykinase 1 (PCK1), the first rate-limiting enzyme in gluconeogenesis, has been implicated in various diseases. However, its role in neuronal damage following CA/CPR remains unclear. To investigate the role of PCK1 in neuronal damage after CA/CPR, we established the CA/CPR animal model and hypoxia/re‑oxygenation (H/R) cell model, manipulated PCK1 expression both in vivo and in vitro. We found increased expression of PCK1 in cortical neurons after CA/CPR. In vivo PCK1 overexpression exacerbated brain injury after CA/CPR via augmenting neuroinflammation and neuronal apoptosis. RNA-sequencing suggested PCK1-OE disturbed the neuronal metabolism while immunoprecipitation/mass spectrometry (IP/MS) revealed that PCK1 contributed to the mitochondrial dysfunction via binding to Voltage-dependent anion-selective channel 1 (VDAC1) and promoting its oligomerization and cytochrome c release. Besides, we confirmed that 3-Mercaptopicolinic acid (3-MPA), the PCK1 inhibitor, could ameliorate the mitochondrial dysfunction and apoptosis of neurons both in vitro and in vivo. For the first time, we identified the detrimental role of PCK1 in post-CA brain injury. During CA/CPR, excessive PCK1 binds to VDAC1, promoting its oligomerization and cytochrome c release which leading to neuronal apoptosis and eventually PCAS. Utilization of 3-MPA during CPR could effectively improve the survival rate and prognosis of mice after CA, which may provide a novel strategy for CA/CPR treatment.
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Affiliation(s)
- Ruochen Xu
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Jingwen Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Jing Zhu
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Fei Guo
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Can Zhang
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Kangyu Chen
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Jian Xu
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
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11
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Ge Y, Jiang L, Dong Q, Xu Y, Yam JWP, Zhong X. Exosome-mediated Crosstalk in the Tumor Immune Microenvironment: Critical Drivers of Hepatocellular Carcinoma Progression. J Clin Transl Hepatol 2025; 13:143-161. [PMID: 39917466 PMCID: PMC11797817 DOI: 10.14218/jcth.2024.00302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.
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Affiliation(s)
- Yifei Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixue Jiang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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12
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Wang K, Li X, Guo S, Chen J, Lv Y, Guo Z, Liu H. Metabolic reprogramming of glucose: the metabolic basis for the occurrence and development of hepatocellular carcinoma. Front Oncol 2025; 15:1545086. [PMID: 39980550 PMCID: PMC11839411 DOI: 10.3389/fonc.2025.1545086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Primary liver cancer is a common malignant tumor of the digestive system, with hepatocellular carcinoma (HCC) being the most prevalent type. It is characterized by high malignancy, insidious onset, and a lack of specific early diagnostic and therapeutic markers, posing a serious threat to human health. The occurrence and development of HCC are closely related to its metabolic processes. Similar to other malignant tumors, metabolic reprogramming occurs extensively in tumor cells, with glucose metabolism reprogramming being particularly prominent. This is characterized by abnormal activation of glycolysis and inhibition of oxidative phosphorylation and gluconeogenesis, among other changes. Glucose metabolism reprogramming provides intermediates and energy for HCC to meet its demands for rapid growth, proliferation, and metastasis. Additionally, various enzymes and signaling molecules involved in glucose metabolism reprogramming play irreplaceable roles. Therefore, regulating key metabolic enzymes and pathways in these processes is considered an important target for the diagnosis and treatment of HCC. This paper reviews the current status and progress of glucose metabolism reprogramming in HCC, aiming to provide new insights for the diagnosis, detection, and comprehensive treatment strategies of HCC involving combined glucose metabolism intervention in clinical settings.
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Affiliation(s)
- Kai Wang
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Xiaodan Li
- Department of Pediatric Health Care, Zhangzi County Maternal and Child Health Family Planning Service Center, Changzhi, Shanxi, China
| | - Shuwei Guo
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Junsheng Chen
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Yandong Lv
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Zhiqiang Guo
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Hongzhou Liu
- Department of Colorectal Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
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13
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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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14
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Zhang C, Zhang X, Dai S, Yang W. Exploring prognosis and therapeutic strategies for HBV-HCC patients based on disulfidptosis-related genes. Front Genet 2025; 15:1522484. [PMID: 39882072 PMCID: PMC11774838 DOI: 10.3389/fgene.2024.1522484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and is the third leading cause of cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is the primary etiological factor. Disulfidptosis is a newly discovered form of regulated cell death. This study aims to develop a novel HBV-HCC prognostic signature related to disulfidptosis and explore potential therapeutic approaches through risk stratification based on disulfidptosis. Methods Transcriptomic data from HBV-HCC patients were analyzed to identify BHDRGs. A prognostic model was established and validated using machine learning, with internal datasets and external datasets for verification. We then performed immune cell infiltration analysis, tumor microenvironment (TME) analysis, and immunotherapy-related analysis based on the prognostic signature. Besides, RT-qPCR and immunohistochemistry were conducted. Results A prognostic model was constructed using five genes (DLAT, STC2, POF1B, S100A9, and CPS1). A corresponding prognostic nomogram was developed based on riskScores, age, stage. Stratification by median risk score revealed a significant correlation between the prognostic signature and TME, tumor immune cell infiltration, immunotherapy efficacy, and drug sensitivity. The results of the experiments indicate that DLAT expression is higher in tumor tissues compared to adjacent tissues. DLAT expression is higher in HBV-HCC tumor tissues compared to normal tissues. Conclusion This study stratifies HBV-HCC patients into distinct subgroups based on BHDRGs, establishing a prognostic model with significant implications for prognosis assessment, TME remodeling, and personalized therapy in HBV-HCC patients.
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Affiliation(s)
| | | | - Shengjie Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenjun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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15
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Wu X, Zhang X, Yu X, Liang H, Tang S, Wang Y. Exploring the association between air pollution and the incidence of liver cancers. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 290:117437. [PMID: 39671760 DOI: 10.1016/j.ecoenv.2024.117437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/15/2024]
Abstract
Liver cancer, namely hepatocellular carcinoma (HCC), is a major global health concern deeply influenced by environmental factors. Air pollutants emerged as significant contributors to its incidence. This review explores the association between air pollution-specifically particulate matter (PM2.5), industrial chemicals like vinyl chloride, and benzene-and the increased risk of liver cancer. Mechanistically, air pollutants may cause liver damage by inducing oxidative stress, inflammation, and genetic mutations, contributing to cancer development. Epidemiological evidence from cohort and geographic studies highlights a positive correlation between long-term exposure to air pollutants and elevated incidence and mortality of liver cancer. Furthermore, air pollution has been shown to worsen survival outcomes in liver cancer patients, particularly those diagnosed at early stages. The review emphasizes the need for stricter air quality regulations and relevant research for underlying mechanisms exposed to air pollution. Addressing air pollution exposure could be crucial for reducing liver cancer risks and improving public health outcomes.
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Affiliation(s)
- Xin Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shengyang, China
| | - Xin Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shengyang, China
| | - Xiaopeng Yu
- Oncology Department, Shengjing Hospital of China Medical University, Shengyang, China
| | - Hongyuan Liang
- Department of Radiology, Shengjing Hospital of China Medical University, Shengyang, China.
| | - Shaoshan Tang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shengyang, China.
| | - Yao Wang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shengyang, China.
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16
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Jia L, Zhang L, Yang H, Li L, Zheng S, Ma Y, Xue Y, Zhang J, Li M, Su X, Wang K. Host-intestinal microbiota interactions in Edwardsiella piscicida-induced lethal enteritis in big-belly seahorses: Novel insights into the role of Carbohydrate-Active enzymes and host transcriptional responses. FISH & SHELLFISH IMMUNOLOGY 2025; 156:110024. [PMID: 39557374 DOI: 10.1016/j.fsi.2024.110024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Edwardsiella piscicida-induced lethal enteritis is a major threat to the sustainable development of seahorse aquaculture. The roles of Carbohydrate-Active enzymes (CAZymes) in interactions between the pathogen and the host are poorly understood. In this study, we found that 22 key CAZymes encoded by E. piscicida might involve in the coordination of five key stages of infection. Specifically, during the motility, adherence, and invasion stages, 10 CAZymes, including CE4, PL8, and CBM48, may significantly increase the activities of Lipid metabolism-associated pathways of the intestinal microbiota (P < 0.01), facilitating pathogen invasion of the host intestinal epithelium. During the replication stage, 11 CAZymes, including GH20, GT4, and GH3, may significantly increase activities of pathways associated with Carbohydrate metabolism (P < 0.01) to promote replication and proliferation of the pathogen. And for avoiding host defenses, GH2 and GH1 may enhance activities of both Carbohydrate and Amino acid metabolic pathways (P < 0.01), facilitating infection and immune evasion. Conjoint analysis showed that E. piscicida might mainly rely on Carbohydrate metabolism for infection, while the host might activate Amino acid metabolic pathways for self-defense. In addition, expressions of 10 key genes, Aldh9a1b, Aoc1, Tpi1b, PCK1, Ldha, Me1, Gla, Cel.2, Ugdh, and Mao, were significantly altered (P < 0.01) and may be used for characterizing host responses to E. piscicida infection. Activities of both Glycolysis/Gluconeogenesis and Tryptophan metabolism were found oppositely changed (P < 0.01) between pathogen and host, respectively, representing the primary focuses of the competition. Overall, this study provides new insights into E. piscicida-mediated intestinal enteritis in fish for the first time from the perspective of CAZymes, as well as a theoretical reference for the prevention and control of these diseases in the aquaculture of seahorses and other fish.
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Affiliation(s)
- Longwu Jia
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Lele Zhang
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Hongwei Yang
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Lin Li
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Shiyi Zheng
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Yicong Ma
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Yuanyuan Xue
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Jingyi Zhang
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Mingzhu Li
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Xiaolei Su
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China
| | - Kai Wang
- School of Fisheries, Ludong University, Yantai, 264025, China; Research and Development Center of Science, Technology and Industrialization of Seahorses, Ludong University, Yantai, 264025, China.
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17
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Mlawer SJ, Pinto FR, Sikes KJ, Connizzo BK. Coordination of Glucose and Glutamine Metabolism in Tendon is Lost in Aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.19.629426. [PMID: 39763790 PMCID: PMC11702705 DOI: 10.1101/2024.12.19.629426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.
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Affiliation(s)
- Samuel J. Mlawer
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, United States
| | - Felicia R. Pinto
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, United States
| | - Katie J. Sikes
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA
| | - Brianne K. Connizzo
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, United States
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18
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Das D, Wang X, Chiu YC, Bouamar H, Sharkey FE, Lopera JE, Lai Z, Weintraub ST, Han X, Zou Y, Chen HIH, Zeballos Torrez CR, Gu X, Cserhati M, Michalek JE, Halff GA, Chen Y, Zheng S, Cigarroa FG, Sun LZ. Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients. J Natl Cancer Inst 2024; 116:1961-1978. [PMID: 39189979 PMCID: PMC11630563 DOI: 10.1093/jnci/djae207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 07/23/2024] [Accepted: 08/20/2024] [Indexed: 08/28/2024] Open
Abstract
BACKGROUND The incidence and mortality rates of hepatocellular carcinoma among Hispanic individuals in the United States are much higher than in non-Hispanic White people. We conducted multi-omics analyses to elucidate molecular alterations in hepatocellular carcinoma among Hispanic patients. METHODS Paired tumor and adjacent nontumor samples were collected from 31 Hispanic hepatocellular carcinomas in South Texas for genomic, transcriptomic, proteomic, and metabolomic profiling. Serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed hepatocellular carcinoma. RESULTS Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in South Texas Hispanic hepatocellular carcinoma patients, suggesting a predominant activation of the Wnt/β-catenin pathway. TERT promoter mutations were also statistically significantly more frequent in the Hispanic cohort (Fisher exact test, P < .05). Cell cycles and liver function were positively and negatively enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in serum samples of hepatocellular carcinoma patients (paired t test, P < .0001). Two hepatocellular carcinoma subtypes from our Hispanic cohort were identified and validated with the Cancer Genome Atlas liver cancer cohort. Patients with better overall survival showed higher activity of immune and angiogenesis signatures and lower activity of liver function-related gene signatures. They also had higher levels of immune checkpoint and immune exhaustion markers. CONCLUSIONS Our study revealed specific molecular features of Hispanic hepatocellular carcinoma and potential biomarkers for therapeutic management. It provides a unique resource for studying Hispanic hepatocellular carcinoma.
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Affiliation(s)
- Debodipta Das
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xiaojing Wang
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yu-Chiao Chiu
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hakim Bouamar
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Francis E Sharkey
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jorge E Lopera
- Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Susan T Weintraub
- Department of Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xianlin Han
- Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yi Zou
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hung-I H Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Carla R Zeballos Torrez
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xiang Gu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Matyas Cserhati
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Joel E Michalek
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Glenn A Halff
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Siyuan Zheng
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Francisco G Cigarroa
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Lu-Zhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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19
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Lu Y, Zhu J, Zhang Y, Li W, Xiong Y, Fan Y, Wu Y, Zhao J, Shang C, Liang H, Zhang W. Lactylation-Driven IGF2BP3-Mediated Serine Metabolism Reprogramming and RNA m6A-Modification Promotes Lenvatinib Resistance in HCC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401399. [PMID: 39450426 PMCID: PMC11633555 DOI: 10.1002/advs.202401399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 09/17/2024] [Indexed: 10/26/2024]
Abstract
Acquired resistance remains a bottleneck for molecular-targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib-resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S-adenosylmethionine (SAM), for N6-methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3-PCK2-SAM-m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2-DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.
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Affiliation(s)
- Yuanxiang Lu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Department of Breast SurgeryZhengzhou University People's HospitalHenan Provincial People's HospitalZhengzhou450003China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
| | - Jinghan Zhu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
| | - Yuxin Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
| | - Wentao Li
- Department of Breast SurgeryZhengzhou University People's HospitalHenan Provincial People's HospitalZhengzhou450003China
| | - Yixiao Xiong
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
- Department of DermatologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei430030China
| | - Yunhui Fan
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
| | - Yang Wu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
| | - Jianping Zhao
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
- Key Laboratory of Organ TransplantationMinistry of EducationNHC Key Laboratory of Organ TransplantationKey Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanHubei430030China
| | - Changzhen Shang
- Department of Hepatobiliary SurgerySun Yat‐sen Memorial Hospital of Sun Yat‐sen UniversityYanjiang West RoadGuangzhou510120China
| | - Huifang Liang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
- Key Laboratory of Organ TransplantationMinistry of EducationNHC Key Laboratory of Organ TransplantationKey Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanHubei430030China
| | - Wanguang Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology1095 Jiefang AvenueWuhanHubei430030China
- Hubei Key Laboratory of Hepato‐Pancreato‐Biliary DiseasesWuhanHubei430030China
- Key Laboratory of Organ TransplantationMinistry of EducationNHC Key Laboratory of Organ TransplantationKey Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhanHubei430030China
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20
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Liu N, Zhu XR, Wu CY, Liu YY, Chen MB, Gu JH. PCK1 as a target for cancer therapy: from metabolic reprogramming to immune microenvironment remodeling. Cell Death Discov 2024; 10:478. [PMID: 39578429 PMCID: PMC11584723 DOI: 10.1038/s41420-024-02240-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024] Open
Abstract
Recently, changes in metabolites and metabolism-related enzymes related to tumor cell proliferation, metastasis, drug resistance, and immunosuppression have become a research hotspot, and researchers have attempted to determine the clinical correlation between specific molecular lesions and metabolic phenotypes. Convincing evidence shows that metabolic reprogramming is closely related to the proliferation, invasion, metastasis, and poor prognosis of malignant tumors. Therefore, targeting metabolic reprogramming is a new direction for cancer treatment. However, how molecular alterations in tumors contribute to metabolic diversity and unique targeting dependencies remains unclear. A full understanding of the underlying mechanisms of metabolic reprogramming in cancer may lead to better identification of therapeutic targets and the development of therapeutic strategies. Evidence for the importance of PCK1, a phosphoenolpyruvate carboxykinase 1, in tumorigenesis and development is accumulating. PCK1 can regulate cell proliferation and metastasis by remodeling cell metabolism. Additionally, PCK1 has "nonclassical" nonmetabolic functions, involving the regulation of gene expression, angiogenesis, epigenetic modification, and other processes, and has an impact on cell survival, apoptosis, and other biological activities, as well as the remodeling of the tumor immune microenvironment. Herein, we provide a comprehensive overview of the functions of PCK1 under physiological and pathological conditions and suggest that PCK1 is a potential target for cancer therapy. We also propose a future exploration direction for targeting PCK1 for cancer therapy from a clinical perspective. Finally, in view of the collective data, the results of our discussion suggest the potential clinical application of targeted PCK1 therapy in combination with chemotherapy and immunotherapy for cancer treatment.
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Affiliation(s)
- Na Liu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
| | - Xiao-Ren Zhu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Chang-Ying Wu
- Department of Intensive Care Medicine, Chongqing People's Hospital, Chongqing, China
| | - Yuan-Yuan Liu
- Clinical Research and Lab Center, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Min-Bin Chen
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
| | - Jin-Hua Gu
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University Kunshan, Kunshan, China.
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21
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Zhao L, Wang L, Wang N, Gao X, Zhang B, Zhao Y, Wang N. Cooking Alters the Metabolites of Onions and Their Ability to Protect Nerve Cells from Lead Damage. Foods 2024; 13:3707. [PMID: 39594122 PMCID: PMC11593875 DOI: 10.3390/foods13223707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
Onions (Allium cepa L.) are nutritious vegetables; however, variations in processing methods can influence their chemical composition and functional properties. Raw processing and cooking are the two main food-processing methods for onions, but it is not clear what kind of changes these two methods cause. In the present study, ultrahigh-resolution liquid chromatography-mass spectrometry (UHPLC-MS) was utilized to observe the changes in onion composition during cooking and to investigate the protective effects of raw and cooked onion extracts against lead damage in vitro and at the cellular level. Many compounds were identified, including amino acids, nucleosides, flavonoids, and organosulfur compounds. Cooking causes changes in the content of numerous amino acids (e.g., DL-glutamine) in onions and increases nucleoside content (e.g., 5'-S-methyl-5'-thioadenosine, adenine). Both raw and cooked onion extracts can reduce neuronal cell damage caused by lead exposure, but cooking increased the free radical scavenging (e.g., DPPH, ABTS, hydroxyl radicals) and chelating of lead ions (up to about 25%) of the onion extracts. In conclusion, cooking can cause changes in the chemical composition of onions and increase their antioxidant and lead chelating capacity.
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Affiliation(s)
- Li Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; (L.Z.); (L.W.); (X.G.)
| | - Liping Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; (L.Z.); (L.W.); (X.G.)
| | - Nan Wang
- College of Food Sciences and Engineering, Ningbo University, Ningbo 315211, China;
| | - Xinchang Gao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; (L.Z.); (L.W.); (X.G.)
| | - Bin Zhang
- Health Science Center, Ningbo University, Ningbo 315211, China;
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; (L.Z.); (L.W.); (X.G.)
- Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo 315211, China
- Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China; (L.Z.); (L.W.); (X.G.)
- Qian Xuesen Collaborative Research Center of Astrochemistry and Space Life Sciences, Ningbo University, Ningbo 315211, China
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22
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Xiao G, Huang X, Huang T, Chen Z, Huang Y, Huang R, Wang X. Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels. Ann Hepatol 2024; 29:101543. [PMID: 39216627 DOI: 10.1016/j.aohep.2024.101543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION AND OBJECTIVES Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels. MATERIALS AND METHODS We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis. RESULTS HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53. CONCLUSIONS These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.
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Affiliation(s)
- Guitao Xiao
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University, 105, Jiuyibei Road, Xin Luo, Longyan, Fujian 364000, PR China
| | - Xiaoyun Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China
| | - Tingxuan Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Zhixin Chen
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Yuehong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China
| | - Rongfeng Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
| | - Xiaozhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, 29, Xinquan Road, Gulou, Fuzhou, Fujian 350001, PR China; Fujian Medical University Cancer Center, Fujian Medical University, 1, Xuefubei Road, Minhou, Fuzhou, Fujian 350001, PR China.
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23
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Zhang Y, Tang X, Liu L, Cai D, Gou S, Hao S, Li Y, Shen J, Chen Y, Zhao Y, Wu X, Li M, Chen M, Li X, Sun Y, Gu L, Li W, Wang F, Zhang Z, Wang X, Deng S, Xiao Z, Yao L, Du F. GLO1 regulates hepatocellular carcinoma proliferation and migration through the cell cycle pathway. BMC Cancer 2024; 24:1297. [PMID: 39434012 PMCID: PMC11492659 DOI: 10.1186/s12885-024-12927-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/10/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a malignant tumor characterized by a high mortality rate. The occurrence and progression of HCC are linked to oxidative stress. Glyoxalase-1 (GLO1) plays an important role in regulating oxidative stress, yet the underlying mechanism remains unclear. GLO1 may serve as a prognostic biomarker and therapeutic target for HCC. METHODS Based on TCGA database hepatocellular carcinoma samples, we conducted a bioinformatics analysis to explore the correlation between GLO1 expression and HCC cell proliferation and viability. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were mainly enriched in the cell cycle pathway. We analyzed the relationships between GLO1 and 24 genes enriched in the cell cycle pathway using a protein-protein interaction (PPI) network. Finally, experimental validation was performed to assess GLO1's impact on the distribution of cells at different cell cycle stages and on the proliferation and migration of HCC cells. RESULTS Our study demonstrated that GLO1 was overexpressed in HCC tissues and was associated with a poor prognosis. Data analysis indicated that overexpression of GLO1 activated the cell cycle pathway and positively correlated with expression of the majority of key cell cycle genes. Experimental validation showed that GLO1 expression affects the number of HCC cells in G2 and S phases and regulates HCC cell proliferation and migration. CONCLUSIONS GLO1 represents a promising therapeutic target for HCC, providing valuable insights into its role in the viability and proliferation of HCC cells.
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Affiliation(s)
- Yao Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Xiaolong Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Lin Liu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Dan Cai
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Shuang Gou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Siyu Hao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Yan Li
- Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Zhuo Zhang
- Key Laboratory of Luzhou City for Aging Medicine, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiaodong Wang
- Department of Hepatobiliary Disease, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China.
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China.
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
| | - Lei Yao
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences, Chengdu, 610072, China.
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China.
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China.
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24
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Chen L, Zhang J, Ding L, Gu T, Andoh V, Ma A, Yao C. Transcriptomics analyses combined with intestinal microorganism survey suggest Resveratrol (RSV) anti-aging and anti-oxidant effects in silkworm (Bombyx mori). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 52:101344. [PMID: 39426068 DOI: 10.1016/j.cbd.2024.101344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/11/2024] [Accepted: 10/12/2024] [Indexed: 10/21/2024]
Abstract
The growing elderly population presents a significant concern, with the prolongation of life expectancy, aging diseases are becoming increasingly common. Resveratrol (RSV) has emerged as a promising compound for disease prevention. However, the effect of RSV on lifespan extension in different organisms, particularly the model organism silkworm, remains inconsistent. We conducted aging experiments using silkworm (B. mori) and employed transcriptomics to investigate the therapeutic effects of RSV on lifespan extension and healthy lifespan in silkworms. RSV increased the survival rate by 8.57 %-12.12 % and enhanced the antioxidant capacity of silkworms. Transcriptomic analysis demonstrated that genes in signaling pathways such as AMPK and FoxO were significantly upregulated. 16SrRNA sequencing of gut contents showed an increase in beneficial bacterial strains under the action of RSV. This study aims to enhance our understanding of lifespan regulation mechanisms using the silkworm model and provide new targets for anti-aging antioxidants research to delay the onset of age-related diseases.
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Affiliation(s)
- Liang Chen
- School of Life Sciences, Jiangsu University, 212013 Zhenjiang, China.
| | - Jiaxin Zhang
- School of Life Sciences, Jiangsu University, 212013 Zhenjiang, China
| | - Lei Ding
- School of Life Sciences, Jiangsu University, 212013 Zhenjiang, China
| | - Tongyu Gu
- School of Life Sciences, Jiangsu University, 212013 Zhenjiang, China
| | - Vivian Andoh
- School of Life Sciences, Jiangsu University, 212013 Zhenjiang, China
| | - Aiqin Ma
- Qingdao Vland Animal Health Group Co., Ltd., Qingdao 266100, China
| | - Chun Yao
- Department of Stomatology, Zhenjiang First People's Hospital, Department of Stomatology, People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, China.
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25
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Tang X, Xue J, Zhang J, Zhou J. A Gluconeogenesis-Related Genes Model for Predicting Prognosis, Tumor Microenvironment Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:1907-1926. [PMID: 39386981 PMCID: PMC11463187 DOI: 10.2147/jhc.s483664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a prevalent malignancy within the digestive system, known for its poor prognosis. Gluconeogenesis, a critical metabolic pathway, is responsible for the synthesis of glucose in the normal liver. This study aimed to examine the role of gluconeogenesis-related genes (GRGs) in HCC and evaluate their impact on the tumor microenvironment infiltration and drug sensitivity in HCC. Methods We retrieved gene expression and clinical pathological data of HCC from The Cancer Genome Atlas (TCGA) database. This dataset was utilized to develop a prognosis model. The data from The International Cancer Genome Consortium (ICGC) served as an independent validation cohort. A least absolute shrinkage and selection operator (LASSO) regression analysis was applied to a curated panel of GRGs to construct and validate the predictive model. Furthermore, unsupervised consensus clustering, based on the expression levels of GRGs, categorized HCC patients into distinct subgroups. Results A four-gene prognostic model, referred to as GRGs, has been successfully developed with high accuracy and stability for the prediction of HCC patient prognosis. This model enables the stratification of patients into high or low risk groups based on individual risk scores, revealing significant differences in immune infiltration patterns and anti-tumor drug responses. Unsupervised consensus clustering analysis delineated four distinct subgroups of patients, each characterized by a unique prognosis and tumor immune microenvironment (TIME). Conclusion This study is the first to develop a prognostic model incorporating 4-GRGs that effectively predicts the prognosis, tumor microenvironment infiltration, and drug sensitivity in HCC patients. The model based on 4 GRGs may contribute to predict the prognosis, immunotherapy and chemotherapy response of HCC patients.
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Affiliation(s)
- Xilong Tang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
- Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
| | - Jianjin Xue
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
- Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
| | - Jie Zhang
- Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
| | - Jiajia Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
- Department of Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China
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Yu H, Wang C, Ke S, Xu Y, Lu S, Feng Z, Bai M, Qian B, Xu Y, Li Z, Yin B, Li X, Hua Y, Zhou M, Li Z, Fu Y, Ma Y. An integrative pan-cancer analysis of MASP1 and the potential clinical implications for the tumor immune microenvironment. Int J Biol Macromol 2024; 280:135834. [PMID: 39307490 DOI: 10.1016/j.ijbiomac.2024.135834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/07/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024]
Abstract
Mannose-binding lectin-associated serine protease 1 (MASP1) plays a crucial role in the complement lectin pathway and the mediation of immune responses. However, comprehensive research on MASP1 across various cancer types has not been performed to date. This study aimed to evaluate the significance of MASP1 in pan-cancer. The Cancer Genome Atlas (TCGA), UCSC Xena and Genotype Tissue Expression (GTEx) databases were used to evaluate the expression profiles, genomic features, prognostic relevance, and immune microenvironment associations of MASP1 across 33 cancer types. We observed significant dysregulation of MASP1 expression in multiple cancers, with strong associations between MASP1 expression levels and diagnostic value as well as patient prognosis. Mechanistic insights revealed significant correlations between MASP1 levels and various immunological and genomic factors, including tumor-infiltrating immune cells (TIICs), immune-related genes, mismatch repair (MMR), tumor mutation burden (TMB), and microsatellite instability (MSI), highlighting a critical regulatory function of MASP1 within the tumor immune microenvironment (TIME). In vitro and in vivo experiments demonstrated that MASP1 expression was markedly decreased in liver hepatocellular carcinoma (LIHC). Moreover, the overexpression of MASP1 in hepatocellular carcinoma (HCC) cell lines significantly inhibited their proliferation, invasion and migration. In conclusion, MASP1 exhibits differential expression in the pan-cancer analyses and might play an important role in TIME. MASP1 is a promising prognostic biomarker and a potential target for immunological research, particularly in LIHC.
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Affiliation(s)
- Hongjun Yu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoqun Wang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Shanjia Ke
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Xu
- Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People's Hospital, Xihu University, Hangzhou, China
| | - Shounan Lu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhigang Feng
- The First Department of General Surgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China
| | - Miaoyu Bai
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baolin Qian
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yue Xu
- Department of Pediatrics, Hainan Hospital of PLA General Hospital, Hainan, China
| | - Zihao Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Yin
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongliang Hua
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Menghua Zhou
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongyu Li
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Fu
- Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Yong Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Minimally Invasive Hepatic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Zhang L, Chen Y, Pan Q, Fang S, Zhang Z, Wang J, Yang Y, Yang D, Sun X. Silencing of PCK1 mitigates the proliferation and migration of vascular smooth muscle cells and vascular intimal hyperplasia by suppressing STAT3/DRP1-mediated mitochondrial fission. Acta Biochim Biophys Sin (Shanghai) 2024; 57:633-645. [PMID: 39262325 PMCID: PMC12040600 DOI: 10.3724/abbs.2024154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/30/2024] [Indexed: 09/13/2024] Open
Abstract
The pathological proliferation and migration of vascular smooth muscle cells (VSMCs) are key processes during vascular neointimal hyperplasia (NIH) and restenosis. Phosphoenolpyruvate carboxy kinase 1 (PCK1) is closely related to a variety of malignant proliferative diseases. However, the role of PCK1 in VSMCs has rarely been investigated. This study aims to examine the role of PCK1 in the proliferation and migration of VSMCs and vascular NIH after injury. In vivo, extensive NIH and increased expression of PCK1 within the neointima are observed in injured arteries. Interestingly, the administration of adeno-associated virus-9 (AAV-9) carrying Pck1 short hairpin RNA (sh Pck1) significantly attenuates NIH and stenosis of the vascular lumen. In vitro, Pck1 small interfering RNA (si Pck1)-induced PCK1 silencing inhibits VSMC proliferation and migration. Additionally, silencing of PCK1 leads to reduced expression of dynamin-related protein 1 (DRP1) and attenuated mitochondrial fission. Lentivirus-mediated DRP1 overexpression markedly reverses the inhibitory effects of PCK1 silencing on VSMC proliferation, migration, and mitochondrial fission. Finally, PCK1 inhibition attenuates the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 abolishes the suppressive effects of PCK1 silencing on DRP1 expression, mitochondrial fission, proliferation, and migration in VSMCs. In conclusion, PCK1 inhibition attenuates the mitochondrial fission, proliferation, and migration of VSMCs by inhibiting the STAT3/DRP1 axis, thereby suppressing vascular NIH and restenosis.
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MESH Headings
- STAT3 Transcription Factor/metabolism
- STAT3 Transcription Factor/genetics
- Cell Proliferation/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/cytology
- Animals
- Cell Movement/genetics
- Mitochondrial Dynamics/genetics
- Dynamins/metabolism
- Dynamins/genetics
- Hyperplasia/metabolism
- Hyperplasia/genetics
- Hyperplasia/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Male
- Neointima/pathology
- Neointima/genetics
- Neointima/metabolism
- Gene Silencing
- Rats
- Rats, Sprague-Dawley
- Cells, Cultured
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Signal Transduction
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Affiliation(s)
- Li Zhang
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Yingmei Chen
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Quanrong Pan
- Department of General Practicethe General Hospital of Western Theater CommandChengdu610083China
| | - Shizheng Fang
- Department of Critical Care Medicinethe General Hospital of Western Theater CommandChengdu610083China
| | - Zhongjian Zhang
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Jia Wang
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Yongjian Yang
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Dachun Yang
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
| | - Xiongshan Sun
- Department of Cardiologythe General Hospital of Western Theater CommandChengdu610083China
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Yan T, Zhang N, Liu F, Wang H, Zhang J, Jin X, Jiang S. PCK2 induces gefitinib resistance by suppresses ferroptosis in non-small cell lung cancer. Biochem Biophys Res Commun 2024; 723:150200. [PMID: 38850814 DOI: 10.1016/j.bbrc.2024.150200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/17/2024] [Accepted: 05/29/2024] [Indexed: 06/10/2024]
Abstract
OBJECTIVES This study aimed to explore the involvement of phosphoenolpyruvate carboxykinase 2 (PCK2) in gefitinib-resistant non-small cell lung cancer (NSCLC) cells and assess its feasibility as a therapeutic target against gefitinib resistance. METHODS Gefitinib-resistant cell lines, PC9GR and HCC827GR, were generated through progressive exposure of parental cells to escalating concentrations of gefitinib. Transcriptomic analysis encompassed the treatment of PC9 and PC9GR cells with gefitinib or vehicle, followed by RNA extraction, sequencing, and subsequent bioinformatic analysis. Cell viability was determined via CCK-8 assay, while clonogenic assays assessed colony formation. Apoptosis was detected utilizing the Annexin V-FITC/7AAD kit. Iron ion concentrations were quantified using FerroOrange. mRNA analysis was conducted through quantitative RT-PCR. Western blotting was employed for protein analysis. H&E and immunohistochemical staining were performed on tumor tissue sections. RESULTS The results revealed that depletion or inhibition of PCK2 significantly enhanced gefitinib's efficacy in inducing cell growth arrest, apoptosis, and ferroptosis in resistant NSCLC. Moreover, PCK2 knockdown led to the downregulation of key ferroptosis-related proteins, GPX4 and SLC7A11, while upregulating ASCL4. Conversely, overexpression of PCK2 in gefitinib-sensitive cells rendered resistance to gefitinib. In vivo experiments using a gefitinib-resistant xenograft model demonstrated that PCK2 silencing not only reduced tumor growth but also considerably increased the anti-tumor effect of gefitinib. CONCLUSIONS In conclusion, our study presents compelling evidence indicating that PCK2 plays a pivotal role in gefitinib resistance in NSCLC. The modulation of ferroptosis-related proteins and the involvement of Akt activation further elucidate the mechanisms underlying this resistance. Consequently, PCK2 emerges as a promising therapeutic target for overcoming gefitinib resistance in NSCLC, offering a new avenue for the development of more effective treatment strategies.
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Affiliation(s)
- Tinghao Yan
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fen Liu
- Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | | | - Jiaqi Zhang
- Jining No.1 People's Hospital, Shandong First Medical University, Jining, China
| | - Xiaohan Jin
- Jining No.1 People's Hospital, Shandong First Medical University, Jining, China; Center for Post-Doctoral Studies, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shulong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China; Jining No.1 People's Hospital, Shandong First Medical University, Jining, China.
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29
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Xie Y, Chen Y, Wu Z, Gong X, Zhang Z, Yang S, Zhang D. Transcriptome analysis of Reticulitermes flaviceps exposed to Mentha spicata essential oil and carvone indicates a potential neurotoxic mechanism of action characterized by intracellular calcium influx mediated by dopamine receptors. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 204:106045. [PMID: 39277372 DOI: 10.1016/j.pestbp.2024.106045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 09/17/2024]
Abstract
Reticulitermes flaviceps is an economically important pest in agriculture, forestry, and construction. Recent studies have shown an increase in research focusing on the anti-termite properties of plant essential oils, however, there remains a lack of information regarding the specific molecular mechanism involved. In this study, RNA-seq analysis was conducted on termites exposed to Mentha spicata essential oil (EO) and carvone, leading to the discovery of various genes that were expressed differentially under different treatment conditions. Numerous genes that exhibited a response to M. spicata EO and carvone found to be associated with stress-related pathways, such as drug metabolism cytochrome P450, glutathione metabolism, fatty acid metabolism, citric acid cycle, neuroactive ligand-receptor interaction, cell apoptosis, the AMPK signalling pathway, the mTOR signalling pathway, the longevity regulation pathway, ubiquitin-mediated protein hydrolysis, and the calcium signalling pathway. The up-regulation of genes (SPHK) associated with calcium channels, such as SPHK, indicates a potential mechanism of neurotoxicity, while the up-regulation of apoptosis-associated genes, including ACTB_G1, PYG, SQSTM1, RNF31, suggests a potential mechanism of cytotoxicity. The metabolism of M. spicata EO induces oxidative stress, elevates free Ca2+ levels in mitochondria, and initiates the generation of reactive oxygen species (ROS), ultimately resulting in programmed cell necrosis and apoptosis, as well as facilitating cellular autophagy. The monoterpenes exhibited neurotoxic and cytotoxic effects on R. flaviceps and could be exploited to advance termiticide development and eco-friendly termite control.
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Affiliation(s)
- Yongjian Xie
- Key Lab for Biology of Crop Pathogens and Insect Pests and Their Ecological Regulation of Zhejiang Province, College of Advanced Agricultural Sciences, Zhejiang A&F University, Hangzhou 311300, PR China.
| | - Yiyang Chen
- Key Lab for Biology of Crop Pathogens and Insect Pests and Their Ecological Regulation of Zhejiang Province, College of Advanced Agricultural Sciences, Zhejiang A&F University, Hangzhou 311300, PR China
| | - Ziwei Wu
- Key Lab for Biology of Crop Pathogens and Insect Pests and Their Ecological Regulation of Zhejiang Province, College of Advanced Agricultural Sciences, Zhejiang A&F University, Hangzhou 311300, PR China
| | - Xue Gong
- Institute of Virology and Biotechnology, Zhejiang Academy of Agricultural Science, Hangzhou 310021, PR China
| | - Zhilin Zhang
- Hubei Key Laboratory of Quality Control of Characteristic Fruits and Vegetables, Hubei Engineering University, Xiaogan 432000, Hubei, PR China
| | - Shimeng Yang
- Key Lab for Biology of Crop Pathogens and Insect Pests and Their Ecological Regulation of Zhejiang Province, College of Advanced Agricultural Sciences, Zhejiang A&F University, Hangzhou 311300, PR China
| | - Dayu Zhang
- Key Lab for Biology of Crop Pathogens and Insect Pests and Their Ecological Regulation of Zhejiang Province, College of Advanced Agricultural Sciences, Zhejiang A&F University, Hangzhou 311300, PR China.
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30
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De Vos K, Mavrogiannis A, Wolters JC, Schlenner S, Wierda K, Cortés Calabuig Á, Chinnaraj R, Dermesrobian V, Armoudjian Y, Jacquemyn M, Corthout N, Daelemans D, Annaert P. Tankyrase1/2 inhibitor XAV-939 reverts EMT and suggests that PARylation partially regulates aerobic activities in human hepatocytes and HepG2 cells. Biochem Pharmacol 2024; 227:116445. [PMID: 39053638 DOI: 10.1016/j.bcp.2024.116445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024]
Abstract
The maintenance of a highly functional metabolic epithelium in vitro is challenging. Metabolic impairments in primary human hepatocytes (PHHs) over time is primarily due to epithelial-to-mesenchymal transitioning (EMT). The immature hepatoma cell line HepG2 was used as an in vitro model to explore strategies for enhancing the hepatic phenotype. The phenotypic characterization includes measuring the urea cycle, lipid storage, tricarboxylic acid-related metabolites, reactive oxygen species, endoplasmic reticulum calcium efflux, mitochondrial membrane potentials, oxygen consumptions rate, and CYP450 biotransformation capacity. Expression studies were performed with transcriptomics, co-immunoprecipitation and proteomics. CRISPR/Cas9 was also employed to genetically engineer HepG2 cells. After confirming that PHHs develop an EMT phenotype, expression of tankyrase1/2 was found to increase over time. EMT was reverted when blocking tankyrases1/2-dependent poly-ADP-ribosylation (PARylation) activity, by biochemical and genetic perturbation. Wnt/β-catenin inhibitor XAV-939 blocks tankyrase1/2 and treatment elevated several oxygen-consuming reactions (electron-transport chain, OXHPOS, CYP450 mono-oxidase activity, phase I/II xenobiotic biotransformation, and prandial turnover), suggesting that cell metabolism was enhanced. Glutathione-dependent redox homeostasis was also significantly improved in the XAV-939 condition. Oxygen consumption rate and proteomics experiments in tankyrase1/2 double knockout HepG2 cells then uncovered PARylation as master regulator of aerobic-dependent cell respiration. Furthermore, novel tankyrase1/2-dependent PARylation targets, including mitochondrial DLST, and OGDH, were revealed. This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.
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Affiliation(s)
- Kristof De Vos
- Laboratory of Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium
| | - Adamantios Mavrogiannis
- Adaptive Immunology, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Justina Clarinda Wolters
- Section Systems Medicine of Metabolism and Signaling, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands
| | - Susan Schlenner
- Adaptive Immunology, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Keimpe Wierda
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Electrophysiology Unit, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | | | - Reena Chinnaraj
- KU Leuven Flow and Mass Cytometry Facility, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Vera Dermesrobian
- KU Leuven Flow and Mass Cytometry Facility, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | | | - Maarten Jacquemyn
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega Institute, 3000 Leuven, Belgium
| | - Nikky Corthout
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; VIB Bio Imaging Core, 3000 Leuven, Belgium
| | - Dirk Daelemans
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega Institute, 3000 Leuven, Belgium
| | - Pieter Annaert
- Laboratory of Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; BioNotus GCV, 2845 Niel, Belgium.
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Xue S, Cai Y, Liu J, Ji K, Yi P, Long H, Zhang X, Li P, Song Y. Dysregulation of phosphoenolpyruvate carboxykinase in cancers: A comprehensive analysis. Cell Signal 2024; 120:111198. [PMID: 38697449 DOI: 10.1016/j.cellsig.2024.111198] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in gluconeogenesis, glycolysis, and the tricarboxylic acid cycle by converting oxaloacetate into phosphoenolpyruvate. Two distinct isoforms of PEPCK, specifically cytosolic PCK1 and mitochondrial PCK2, have been identified. Nevertheless, the comprehensive understanding of their dysregulation in pan-cancer and their potential mechanism contributing to signaling transduction pathways remains elusive. METHODS We conducted comprehensive analyses of PEPCK gene expression across 33 diverse cancer types using data from The Cancer Genome Atlas (TCGA). Multiple public databases such as HPA, TIMER 2.0, GEPIA2, cBioPortal, UALCAN, CancerSEA, and String were used to investigate protein levels, prognostic significance, clinical associations, genetic mutations, immune cell infiltration, single-cell sequencing, and functional enrichment analysis in patients with pan-cancer. PEPCK expression was analyzed about different clinical and genetic factors of patients using data from TCGA, GEO, and CGGA databases. Furthermore, the role of PCK2 in Glioma was examined using both in vitro and in vivo experiments. RESULTS The analysis we conducted revealed that the expression of PEPCK is involved in both clinical outcomes and immune cell infiltration. Initially, we verified the high expression of PCK2 in GBM cells and its role in metabolic reprogramming and proliferation in GBM. CONCLUSION Our study showed a correlation between PEPCK (PCK1 and PCK2) expression with clinical prognosis, gene mutation, and immune infiltrates. These findings identified two possible predictive biomarkers across different cancer types, as well as a comprehensive analysis of PCK2 expression in various tumors, with a focus on GBM.
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Affiliation(s)
- Shuaishuai Xue
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yonghua Cai
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jun Liu
- Department of Neurosurgery, The 2(nd) affiliated hospital Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330000, China
| | - Ke Ji
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Peiyao Yi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hao Long
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xian Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Peng Li
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Ye Song
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Pang H, Zhang W, Lin X, Zeng F, Xiao X, Wei Z, Wang S, Jian J, Wang N, Li W. Vibrio alginolyticus PEPCK Mediates Florfenicol Resistance through Lysine Succinylation Modification. J Proteome Res 2024; 23:2397-2407. [PMID: 38904328 DOI: 10.1021/acs.jproteome.4c00085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Protein succinylation modification is a common post-translational modification (PTM) that plays an important role in bacterial metabolic regulation. In this study, quantitative analysis was conducted on the succinylated proteome of wild-type and florfenicol-resistant Vibrio alginolyticus to investigate the mechanism of succinylation regulating antibiotic resistance. Bioinformatic analysis showed that the differentially succinylated proteins were mainly enriched in energy metabolism, and it was found that the succinylation level of phosphoenolpyruvate carboxyl kinase (PEPCK) was highly expressed in the florfenicol-resistant strain. Site-directed mutagenesis was used to mutate the lysine (K) at the succinylation site of PEPCK to glutamic acid (E) and arginine (R), respectively, to investigate the function of lysine succinylation of PEPCK in the florfenicol resistance of V. alginolyticus. The detection of site-directed mutagenesis strain viability under florfenicol revealed that the survival rate of the E mutant was significantly higher than that of the R mutant and wild type, indicating that succinylation modification of PEPCK protein may affect the resistance of V. alginolyticus to florfenicol. This study indicates the important role of PEPCK during V. alginolyticus antibiotic-resistance evolution and provides a theoretical basis for the prevention and control of vibriosis and the development of new antibiotics.
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Affiliation(s)
- Huanying Pang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Weijie Zhang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Xuelian Lin
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Fuyuan Zeng
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Xing Xiao
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Zhiqing Wei
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Shi Wang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Jichang Jian
- Fisheries College, Guangdong Ocean University, Zhanjiang 524025, China
- Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture and Key Laboratory of Control for Diseases of Aquatic Economic Animals of Guangdong Higher Education Institutes, Zhanjiang 524025, Guangdong, China
| | - Na Wang
- Chinese Academy of Inspection and Quarantine, Beijing 100176, China
| | - Wanxin Li
- School of Public Health, Fujian Medical University, Fujian 350122, China
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Liu R, Liu Y, Zhang W, Zhang G, Zhang Z, Huang L, Tang N, Wang K. PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma. Genes Dis 2024; 11:101114. [PMID: 38560500 PMCID: PMC10978540 DOI: 10.1016/j.gendis.2023.101114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 06/19/2023] [Accepted: 08/04/2023] [Indexed: 04/04/2024] Open
Abstract
Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.
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Affiliation(s)
- Rui Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Yi Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Wenlu Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Guiji Zhang
- Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, China
| | - Zhirong Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Luyi Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
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Li C, Zhang ED, Ye Y, Xiao Z, Huang H, Zeng Z. Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma. Sci Rep 2024; 14:14051. [PMID: 38890507 PMCID: PMC11189538 DOI: 10.1038/s41598-024-64907-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 06/14/2024] [Indexed: 06/20/2024] Open
Abstract
Mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a mitochondrial isoenzyme, supports the growth of cancer cells under glucose deficiency conditions in vitro. This study investigated the role and potential mechanism of PCK2 in the occurrence and development of Hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases distinguish the expression of PCK2 and verified by qRT-PCR and Western blotting. Kaplan-Meier was conducted to assess PCK2 survival in HCC. The potential biological function of PCK2 was verified by enrichment analysis and gene set enrichment analysis (GSEA). The correlation between PCK2 expression and immune invasion and checkpoint was found by utilizing Tumor Immune Estimation Resource (TIMER). Lastly, the effects of PCK2 on the proliferation and metastasis of hepatocellular carcinoma cells were evaluated by cell tests, and the expressions of Epithelial mesenchymal transformation (EMT) and apoptosis related proteins were detected. PCK2 is down-regulated in HCC, indicating a poor prognosis. PCK2 gene mutation accounted for 1.3% of HCC. Functional enrichment analysis indicated the potential of PCK2 as a metabolism-related therapeutic target. Subsequently, we identified several signaling pathways related to the biological function of PCK2. The involvement of PCK2 in immune regulation was verified and key immune checkpoints were predicted. Ultimately, after PCK2 knockdown, cell proliferation and migration were significantly increased, and N-cadherin and vimentin expression were increased. PCK2 has been implicated in immune regulation, proliferation, and metastasis of hepatocellular carcinoma, and is emerging as a novel predictive biomarker and metabolic-related clinical target.
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Affiliation(s)
| | | | - Youzhi Ye
- Kunming Medical University, Kunming, China
| | | | - Hanfei Huang
- The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.
| | - Zhong Zeng
- The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, China.
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Li A, Wang R, Zhao Y, Zhao P, Yang J. Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight. Metabolites 2024; 14:325. [PMID: 38921460 PMCID: PMC11205353 DOI: 10.3390/metabo14060325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/01/2024] [Accepted: 06/05/2024] [Indexed: 06/27/2024] Open
Abstract
Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.
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Affiliation(s)
- Anqi Li
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (A.L.); (Y.Z.); (P.Z.)
| | - Rui Wang
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150040, China;
- Key Laboratory of Basic and Application Research of Beiyao, Heilongjiang University of Chinese Medicine, Ministry of Education, Harbin 150040, China
| | - Yuqiang Zhao
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (A.L.); (Y.Z.); (P.Z.)
| | - Peiran Zhao
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (A.L.); (Y.Z.); (P.Z.)
| | - Jing Yang
- College of Basic Medical Science, Heilongjiang University of Chinese Medicine, Harbin 150040, China; (A.L.); (Y.Z.); (P.Z.)
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Bajinka O, Ouedraogo SY, Golubnitschaja O, Li N, Zhan X. Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine. EPMA J 2024; 15:289-319. [PMID: 38841622 PMCID: PMC11147999 DOI: 10.1007/s13167-024-00357-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 03/20/2024] [Indexed: 06/07/2024]
Abstract
Energy metabolism is a hub of governing all processes at cellular and organismal levels such as, on one hand, reparable vs. irreparable cell damage, cell fate (proliferation, survival, apoptosis, malignant transformation etc.), and, on the other hand, carcinogenesis, tumor development, progression and metastazing versus anti-cancer protection and cure. The orchestrator is the mitochondria who produce, store and invest energy, conduct intracellular and systemically relevant signals decisive for internal and environmental stress adaptation, and coordinate corresponding processes at cellular and organismal levels. Consequently, the quality of mitochondrial health and homeostasis is a reliable target for health risk assessment at the stage of reversible damage to the health followed by cost-effective personalized protection against health-to-disease transition as well as for targeted protection against the disease progression (secondary care of cancer patients against growing primary tumors and metastatic disease). The energy reprogramming of non-small cell lung cancer (NSCLC) attracts particular attention as clinically relevant and instrumental for the paradigm change from reactive medical services to predictive, preventive and personalized medicine (3PM). This article provides a detailed overview towards mechanisms and biological pathways involving metabolic reprogramming (MR) with respect to inhibiting the synthesis of biomolecules and blocking common NSCLC metabolic pathways as anti-NSCLC therapeutic strategies. For instance, mitophagy recycles macromolecules to yield mitochondrial substrates for energy homeostasis and nucleotide synthesis. Histone modification and DNA methylation can predict the onset of diseases, and plasma C7 analysis is an efficient medical service potentially resulting in an optimized healthcare economy in corresponding areas. The MEMP scoring provides the guidance for immunotherapy, prognostic assessment, and anti-cancer drug development. Metabolite sensing mechanisms of nutrients and their derivatives are potential MR-related therapy in NSCLC. Moreover, miR-495-3p reprogramming of sphingolipid rheostat by targeting Sphk1, 22/FOXM1 axis regulation, and A2 receptor antagonist are highly promising therapy strategies. TFEB as a biomarker in predicting immune checkpoint blockade and redox-related lncRNA prognostic signature (redox-LPS) are considered reliable predictive approaches. Finally, exemplified in this article metabolic phenotyping is instrumental for innovative population screening, health risk assessment, predictive multi-level diagnostics, targeted prevention, and treatment algorithms tailored to personalized patient profiles-all are essential pillars in the paradigm change from reactive medical services to 3PM approach in overall management of lung cancers. This article highlights the 3PM relevant innovation focused on energy metabolism as the hub to advance NSCLC management benefiting vulnerable subpopulations, affected patients, and healthcare at large. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-024-00357-5.
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Affiliation(s)
- Ousman Bajinka
- Medical Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Serge Yannick Ouedraogo
- Medical Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, University Hospital Bonn, Venusberg Campus 1, Rheinische Friedrich-Wilhelms-University of Bonn, 53127 Bonn, Germany
| | - Na Li
- Medical Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
| | - Xianquan Zhan
- Medical Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
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de Zeeuw P, Treps L, García-Caballero M, Harjes U, Kalucka J, De Legher C, Brepoels K, Peeters K, Vinckier S, Souffreau J, Bouché A, Taverna F, Dehairs J, Talebi A, Ghesquière B, Swinnen J, Schoonjans L, Eelen G, Dewerchin M, Carmeliet P. The gluconeogenesis enzyme PCK2 has a non-enzymatic role in proteostasis in endothelial cells. Commun Biol 2024; 7:618. [PMID: 38783087 PMCID: PMC11116505 DOI: 10.1038/s42003-024-06186-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 04/11/2024] [Indexed: 05/25/2024] Open
Abstract
Endothelial cells (ECs) are highly glycolytic, but whether they generate glycolytic intermediates via gluconeogenesis (GNG) in glucose-deprived conditions remains unknown. Here, we report that glucose-deprived ECs upregulate the GNG enzyme PCK2 and rely on a PCK2-dependent truncated GNG, whereby lactate and glutamine are used for the synthesis of lower glycolytic intermediates that enter the serine and glycerophospholipid biosynthesis pathways, which can play key roles in redox homeostasis and phospholipid synthesis, respectively. Unexpectedly, however, even in normal glucose conditions, and independent of its enzymatic activity, PCK2 silencing perturbs proteostasis, beyond its traditional GNG role. Indeed, PCK2-silenced ECs have an impaired unfolded protein response, leading to accumulation of misfolded proteins, which due to defective proteasomes and impaired autophagy, results in the accumulation of protein aggregates in lysosomes and EC demise. Ultimately, loss of PCK2 in ECs impaired vessel sprouting. This study identifies a role for PCK2 in proteostasis beyond GNG.
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Affiliation(s)
- Pauline de Zeeuw
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
- Droia Ventures, Zaventem, Belgium
| | - Lucas Treps
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
- CNRS, Nantes, France
| | - Melissa García-Caballero
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
- Dept. Molecular Biology and Biochemistry, Fac. Science, University of Malaga, Malaga, Spain
| | - Ulrike Harjes
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Joanna Kalucka
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
- Aarhus Institute of Advanced Studies (AIAS), Department of Biomedicine, Aarhus University, Aarhus, 8000, Denmark
| | - Carla De Legher
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Katleen Brepoels
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Kristel Peeters
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Stefan Vinckier
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Joris Souffreau
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Ann Bouché
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Federico Taverna
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
- Novartis Ireland, Dublin, Ireland
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
| | - Ali Talebi
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
| | - Bart Ghesquière
- Metabolomics Core Facility, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Metabolomics Core Facility, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Johan Swinnen
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium
| | - Guy Eelen
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium.
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium.
- Metaptys NV/Droia Labs, Leuven, Belgium.
| | - Mieke Dewerchin
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium.
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium.
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, B-3000, Belgium.
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, B-3000, Belgium.
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
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Hu N, Li H, Tao C, Xiao T, Rong W. The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:5584. [PMID: 38891772 PMCID: PMC11171976 DOI: 10.3390/ijms25115584] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.
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Affiliation(s)
- Nan Hu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Haiyang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Changcheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
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Tian Z, Song J, She J, He W, Guo S, Dong B. Constructing a disulfidptosis-related prognostic signature of hepatocellular carcinoma based on single-cell sequencing and weighted co-expression network analysis. Apoptosis 2024:10.1007/s10495-024-01968-z. [PMID: 38760515 DOI: 10.1007/s10495-024-01968-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2024] [Indexed: 05/19/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks as the second leading cause of cancer-related deaths globally. Disulfidptosis is a newly identified form of regulated cell death that is induced by glucose starvation. However, the clinical prognostic characteristics of disulfidptosis-associated genes in HCC remain poorly understood. We conducted an analysis of the single-cell datasets GSE149614 and performed weighted co-expression network analysis (WGCNA) on the Cancer Genome Atlas (TCGA) datasets to identify the genes related to disulfidptosis. A prognostic model was constructed using univariate COX and Lasso regression. Survival analysis, immune microenvironment analysis, and mutation analysis were performed. Additionally, a nomogram associated with disulfidptosis-related signature was constructed to identify the prognosis of HCC patients. Patients with HCC in the TCGA and GSE14520 datasets were categorized using a disulfidptosis-related model, revealing significant differences in survival times between the high- and low-disulfidptosis groups. High-disulfidptosis patients exhibited increased expression of immune checkpoint-related genes, implying that immunotherapy and certain chemotherapies may be beneficial for them. Meanwhile, the ROC and decision curves analysis (DCA) indicated that the nomogram has satisfying prognostic efficacy. Moreover, the experimental results of GATM in this prognostic model indicated that GATM is low expressed in HCC tissues, and GATM knockdown promotes the proliferation and migration of HCC cells. By analyzing single-cell and bulk multi-omics sequencing data, we developed a prognostic signature related to disulfidptosis and explored the relationship between high- and low-disulfidptosis groups in HCC. This study offers a novel reference for gaining a deeper understanding of the role of disulfidptosis in HCC.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Junbo Song
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Jiang She
- Department of Orthopedics, Ninth Hospital of Xi'an, Xi'an, 710000, Shaanxi, China
| | - Weixiang He
- Department of Urology, Air Force Medical University, Xi'an, China
| | - Shanshan Guo
- Department of Physiology and Pathophysiology, Air Force Medical University, Xi'an, China
| | - Bingchen Dong
- Department of Orthopedics, Ninth Hospital of Xi'an, Xi'an, 710000, Shaanxi, China.
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Yin N, Xu B, Huang Z, Fu Y, Huang H, Fan J, Huang C, Mei Q, Zeng Y. Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis. FASEB J 2024; 38:e23618. [PMID: 38651689 DOI: 10.1096/fj.202400039r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/22/2024] [Accepted: 04/04/2024] [Indexed: 04/25/2024]
Abstract
Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.
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Affiliation(s)
- Nuoming Yin
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Binqiang Xu
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zehua Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yang Fu
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Huizheng Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Junjie Fan
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chunlan Huang
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Qixiang Mei
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yue Zeng
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai JiaoTong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
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Das D, Wang X, Chiu YC, Bouamar H, Sharkey FE, Lopera JE, Lai Z, Weintraub ST, Han X, Zou Y, Chen HIH, Zeballos Torrez CR, Gu X, Cserhati M, Michalek JE, Halff GA, Chen Y, Zheng S, Cigarroa FG, Sun LZ. Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.04.27.24306447. [PMID: 38746245 PMCID: PMC11092709 DOI: 10.1101/2024.04.27.24306447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Background The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/β-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.
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Bi HE, Zhang J, Yao Y, Wang S, Yao J, Shao Z, Jiang Q. Expression and functional significance of phosphoenolpyruvate carboxykinase 1 in uveal melanoma. Cell Death Discov 2024; 10:196. [PMID: 38670942 PMCID: PMC11053060 DOI: 10.1038/s41420-024-01963-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Uveal melanoma (UVM), an uncommon yet potentially life-threatening ocular cancer, arises from melanocytes in the uveal tract of the eye. The exploration of novel oncotargets for UVM is of paramount importance. In this study, we show that PCK1 (phosphoenolpyruvate carboxykinase 1) expression is upregulated in various UVM tissues as well as in primary UVM cells and immortalized lines. Furthermore, bioinformatics studies reveal that PCK1 overexpression in UVM correlates with advanced disease stages and poor patient survival. Genetic silencing (utilizing viral shRNA) or knockout (via CRISPR/Cas9) of PCK1 significantly curtailed cell viability, proliferation, cell cycle progression, and motility, while provoking apoptosis in primary and immortalized UVM cells. Conversely, ectopic overexpression of PCK1, achieved through a viral construct, bolstered UVM cell proliferation and migration. Gαi3 expression and Akt phosphorylation were reduced following PCK1 silencing or knockout, but increased after PCK1 overexpression in UVM cells. Restoring Akt phosphorylation through a constitutively active mutant Akt1 (S473D) ameliorated the growth inhibition, migration suppression, and apoptosis induced by PCK1 silencing in UVM cells. Additionally, ectopic expression of Gαi3 restored Akt activation and counteracted the anti-UVM cell effects by PCK1 silencing. In vivo, the growth of subcutaneous xenografts of primary human UVM cells was significantly inhibited following intratumoral injection of adeno-associated virus (aav) expressing PCK1 shRNA. PCK1 depletion, Gαi3 downregulation, Akt inhibition, proliferation arrest, and apoptosis were detected in PCK1-silenced UVM xenografts. Collectively, our findings demonstrate that PCK1 promotes UVM cell growth possibly by modulating the Gαi3-Akt signaling pathway.
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Affiliation(s)
- Hui-E Bi
- The Affiliated Eye Hospital, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Department of Ophthalmology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jie Zhang
- Obstetrics and Gynecology Department, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Yujia Yao
- The Affiliated Eye Hospital, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Suyu Wang
- The Affiliated Eye Hospital, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Jin Yao
- The Affiliated Eye Hospital, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
| | - Zhijiang Shao
- Department of Ophthalmology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
| | - Qin Jiang
- The Affiliated Eye Hospital, The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
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Hori Y, Yoh T, Nishino H, Okura K, Kurimoto M, Takamatsu Y, Satoh M, Nishio T, Koyama Y, Ishii T, Iwaisako K, Seo S, Hatano E. Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma. Carcinogenesis 2024; 45:119-130. [PMID: 38123365 DOI: 10.1093/carcin/bgad094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/24/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023] Open
Abstract
The role of the ferroptosis-related gene glutathione peroxidase 4 (GPX4) in oncology has been extensively investigated. However, the clinical implications of GPX4 in patients with intrahepatic cholangiocarcinoma (ICC) remain unknown. This study aimed to evaluate the prognostic impact of GPX4 and its underlying molecular mechanisms in patients with ICC. Fifty-seven patients who underwent surgical resection for ICC between 2010 and 2017 were retrospectively analyzed. Based on the immunohistochemistry, patients were divided into GPX4 high (n = 15) and low (n = 42) groups, and clinical outcomes were assessed. Furthermore, the roles of GPX4 in cell proliferation, migration and gene expression were analyzed in ICC cell lines in vitro and in vivo. The results from clinical study showed that GPX4 high group showed significant associations with high SUVmax on 18F-fluorodeoxyglucose-positron emission tomography (≥8.0, P = 0.017), multiple tumors (P = 0.004), and showed glucose transporter 1 (GLUT1) high expression with a trend toward significance (P = 0.053). Overall and recurrence-free survival in the GPX4 high expression group were significantly worse than those in the GPX4 low expression group (P = 0.038 and P < 0.001, respectively). In the experimental study, inhibition of GPX4 attenuated cell proliferation and migration in ICC cell lines. Inhibition of GPX4 also decreased the expression of glucose metabolism-related genes, such as GLUT1 or HIF1α. Mechanistically, these molecular changes are regulated in Akt-mechanistic targets of rapamycin axis. In conclusion, this study suggested the pivotal value of GPX4 serving as a prognostic marker for patients with ICC. Furthermore, GPX4 can mediate glucose metabolism of ICC.
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Affiliation(s)
- Yutaro Hori
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoaki Yoh
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroto Nishino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keisuke Okura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Makoto Kurimoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuichi Takamatsu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Motohiko Satoh
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Nishio
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Science, Doshisha University, Kyotanabe, Japan
| | - Satoru Seo
- Department of Surgery, Faculty of Medicine, Kochi Medical School, Nankoku, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Liu B, Dou J, Cao J. Nuclear respiratory factor 1 regulates super enhancer-controlled SPIDR to protect hepatocellular carcinoma cells from oxidative stress. BMC Gastroenterol 2024; 24:97. [PMID: 38438958 PMCID: PMC10913589 DOI: 10.1186/s12876-024-03183-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Cellular response to oxidative stress plays significant roles in hepatocellular carcinoma (HCC) development, yet the exact mechanism by which HCC cells respond to oxidative stress remains poorly understood. This study aimed to investigate the role and mechanism of super enhancer (SE)-controlled genes in oxidative stress response of HCC cells. METHODS The GSE112221 dataset was used to identify SEs by HOMER. Functional enrichment of SE-controlled genes was performed by Metascape. Transcription factors were predicted using HOMER. Prognosis analysis was conducted using the Kaplan-Meier Plotter website. Expression correlation analysis was performed using the Tumor Immune Estimation Resource web server. NRF1 and SPIDR expression in HCC and normal liver tissues was analyzed based on the TCGA-LIHC dataset. ChIP-qPCR was used to detect acetylation of lysine 27 on histone 3 (H3K27ac) levels of SE regions of genes, and the binding of NRF1 to the SE of SPIDR. To mimic oxidative stress, HepG2 and Hep3B cells were stimulated with H2O2. The effects of NRF1 and SPIDR on the oxidative stress response of HCC cells were determined by the functional assays. RESULTS A total of 318 HCC-specific SE-controlled genes were identified. The functions of these genes was significant association with oxidative stress response. SPIDR and RHOB were enriched in the "response to oxidative stress" term and were chosen for validation. SE regions of SPIDR and RHOB exhibited strong H3K27ac modification, which was significantly inhibited by JQ1. JQ1 treatment suppressed the expression of SPIDR and RHOB, and increased reactive oxygen species (ROS) levels in HCC cells. TEAD2, TEAD3, NRF1, HINFP and TCFL5 were identified as potential transcription factors for HCC-specific SE-controlled genes related to oxidative stress response. The five transcription factors were positively correlated with SPIDR expression, with the highest correlation coefficient for NRF1. NRF1 and SPIDR expression was up-regulated in HCC tissues and cells. NRF1 activated SPIDR transcription by binding to its SE. Silencing SPIDR or NRF1 significantly promoted ROS accumulation in HCC cells. Under oxidative stress, silencing SPIDR or NRF1 increased ROS, malondialdehyde (MDA) and γH2AX levels, and decreased superoxide dismutase (SOD) levels and cell proliferation of HCC cells. Furthermore, overexpression of SPIDR partially offset the effects of NRF1 silencing on ROS, MDA, SOD, γH2AX levels and cell proliferation of HCC cells. CONCLUSION NRF1 driven SPIDR transcription by occupying its SE, protecting HCC cells from oxidative stress-induced damage. NRF1 and SPIDR are promising biomarkers for targeting oxidative stress in the treatment of HCC.
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Affiliation(s)
- Baowang Liu
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, 050051, Shijiazhuang, Hebei, China
| | - Jian Dou
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, 050051, Shijiazhuang, Hebei, China.
| | - Jinglin Cao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, 050051, Shijiazhuang, Hebei, China.
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Cui Y, Jiang N. CDCA8 Facilitates Tumor Proliferation and Predicts a Poor Prognosis in Hepatocellular Carcinoma. Appl Biochem Biotechnol 2024; 196:1481-1492. [PMID: 37428386 DOI: 10.1007/s12010-023-04603-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2023] [Indexed: 07/11/2023]
Abstract
CDCA8 expression is abnormally high in a variety of cancers and involved in the biological process of tumor malignancy. In this study, we discovered that the expression of CDCA8 was up-regulated in hepatocellular carcinoma cancer (HCC) tissues and high levels of CDCA8 are associated with larger tumor size, higher AFP (α-fetoprotein) levels, and unfavorable prognosis. Cell functional experiments revealed that CDCA8 silencing remarkably inhibited proliferation and promoted apoptosis in SNU-387 and Hep-3B cells. The results of flow cytometry showed that CDCA8 regulated CDK1 and cyclin B1 expression to arrest at the S phase, inhibited proliferation, and promoted apoptosis. In addition, in vivo studies have confirmed that silencing CDCA8 could regulate CDK1/cyclin B1 signaling axis to inhibit the growth of HCC xenograft tumor. Our study demonstrated CDCA8 acts an oncogene to facilitate cell proliferation of HCC via regulating cell cycle, indicating the promising application value of CDCA8 for HCC diagnosis and clinical treatment.
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Affiliation(s)
- Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Ning Jiang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin University of Sport, No.16 Donghai Road, West Tuanbo New Town, Jinghai District, Tianjin, China.
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Zhao PW, Cui JX, Wang XM. Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis. THE PHARMACOGENOMICS JOURNAL 2024; 24:5. [PMID: 38378770 DOI: 10.1038/s41397-024-00324-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/22/2024]
Abstract
OBJECTIVE To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. RESULTS In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. CONCLUSIONS In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.
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Affiliation(s)
- Peng-Wei Zhao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, No.5 Xinhua Street, Huimin District, Hohhot, 010059, China
| | - Jia-Xian Cui
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, No.5 Xinhua Street, Huimin District, Hohhot, 010059, China
| | - Xiu-Mei Wang
- Medical Oncology, Affiliated Cancer Hospital of Inner Mongolia Medical University, No. 42 Zhaowuda Road, Saihan District, Hohhot, 010020, Inner Mongolia, China.
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Lu L, Yang Y, Shi G, He X, Xu X, Feng Y, Wang W, Li Z, Yang J, Li B, Sun G. Alterations in mitochondrial structure and function in response to environmental temperature changes in Apostichopus japonicus. MARINE ENVIRONMENTAL RESEARCH 2024; 194:106330. [PMID: 38171258 DOI: 10.1016/j.marenvres.2023.106330] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/07/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024]
Abstract
Global temperatures have risen as a result of climate change, and the resulting warmer seawater will exert physiological stresses on many aquatic animals, including Apostichopus japonicus. It has been suggested that the sensitivity of aquatic poikilothermal animals to climate change is closely related to mitochondrial function. Therefore, understanding the interaction between elevated temperature and mitochondrial functioning is key to characterizing organisms' responses to heat stress. However, little is known about the mitochondrial response to heat stress in A. japonicus. In this work, we investigated the morphological and functional changes of A. japonicus mitochondria under three representative temperatures, control temperature (18 °C), aestivation temperature (25 °C) and heat stress temperature (32 °C) temperatures using transmission electron microscopy (TEM) observation of mitochondrial morphology combined with proteomics and metabolomics techniques. The results showed that the mitochondrial morphology of A. japonicus was altered, with decreases in the number of mitochondrial cristae at 25 °C and mitochondrial lysis, fracture, and vacuolization at 32 °C. Proteomic and metabolomic analyses revealed 103 differentially expressed proteins and 161 differential metabolites at 25 °C. At 32 °C, the levels of 214 proteins and 172 metabolites were significantly altered. These proteins and metabolites were involved in the tricarboxylic acid (TCA) cycle, substance transport, membrane potential homeostasis, anti-stress processes, mitochondrial autophagy, and apoptosis. Furthermore, a hypothetical network of proteins and metabolites in A. japonicus mitochondria in response to temperature changes was constructed based on proteomic and metabolomic data. These results suggest that the dynamic regulation of mitochondrial energy metabolism, resistance to oxidative stress, autophagy, apoptosis, and mitochondrial morphology in A. japonicus may play important roles in the response to elevated temperatures. In summary, this study describes the response of A. japonicus mitochondria to temperature changes from the perspectives of morphology, proteins, and metabolites, which provided a better understanding the mechanisms of mitochondrial regulation under environment stress in marine echinoderms.
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Affiliation(s)
- Lixin Lu
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Yu Yang
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Guojun Shi
- Hekou District Science and Technology Bureau, China
| | - Xiaohua He
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Xiaohui Xu
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Yanwei Feng
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Weijun Wang
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Zan Li
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Jianmin Yang
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China
| | - Bin Li
- Yantai Haiyu Marine Science and Technology Co. Ltd, Yantai, 264002, China
| | - Guohua Sun
- School of Agriculture, Ludong University, Yantai, Shandong, 264025, China.
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Miao C, He X, Chen G, Kahlert UD, Yao C, Shi W, Su D, Hu L, Zhang Z. Seven oxidative stress-related genes predict the prognosis of hepatocellular carcinoma. Aging (Albany NY) 2023; 15:15050-15063. [PMID: 38097352 PMCID: PMC10781471 DOI: 10.18632/aging.205330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/06/2023] [Indexed: 01/07/2024]
Abstract
Predicting the prognosis of hepatocellular carcinoma (HCC) is a major medical challenge and of guiding significance for treatment. This study explored the actual relevance of RNA expression in predicting HCC prognosis. Cox's multiple regression was used to establish a risk score staging classification and to predict the HCC patients' prognosis on the basis of data in the Cancer Genome Atlas (TCGA). We screened seven gene biomarkers related to the prognosis of HCC from the perspective of oxidative stress, including Alpha-Enolase 1(ENO1), N-myc downstream-regulated gene 1 (NDRG1), nucleophosmin (NPM1), metallothionein-3, H2A histone family member X, Thioredoxin reductase 1 (TXNRD1) and interleukin 33 (IL-33). Among them we measured the expression of ENO1, NGDP1, NPM1, TXNRD1 and IL-33 to investigate the reliability of the multi-index prediction. The first four markers' expressions increased successively in the paracellular tissues, the hepatocellular carcinoma samples (from patients with better prognosis) and the hepatocellular carcinoma samples (from patients with poor prognosis), while IL-33 showed the opposite trend. The seven genes increased the sensitivity and specificity of the predictive model, resulting in a significant increase in overall confidence. Compared with the patients with higher-risk scores, the survival rates with lower-risk scores are significantly increased. Risk score is more accurate in predicting the prognosis HCC patients than other clinical factors. In conclusion, we use the Cox regression model to identify seven oxidative stress-related genes, investigate the reliability of the multi-index prediction, and develop a risk staging model for predicting the prognosis of HCC patients and guiding precise treatment strategy.
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Affiliation(s)
- Chen Miao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiao He
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ulf D. Kahlert
- Molecular and Experimental Surgery, Clinic for General-, Visceral-, Vascular and Transplant Surgery, Faculty of Medicine and University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Chenchen Yao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjie Shi
- Molecular and Experimental Surgery, Clinic for General-, Visceral-, Vascular and Transplant Surgery, Faculty of Medicine and University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China
- Department of Pathology and Clinical Laboratory, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Liang Hu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Ferreira B, Heredia A, Serpa J. An integrative view on glucagon function and putative role in the progression of pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC). Mol Cell Endocrinol 2023; 578:112063. [PMID: 37678603 DOI: 10.1016/j.mce.2023.112063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/16/2023] [Accepted: 09/02/2023] [Indexed: 09/09/2023]
Abstract
Cancer metabolism research area evolved greatly, however, is still unknown the impact of systemic metabolism control and diet on cancer. It makes sense that systemic regulators of metabolism can act directly on cancer cells and activate signalling, prompting metabolic remodelling needed to sustain cancer cell survival, tumour growth and disease progression. In the present review, we describe the main glucagon functions in the control of glycaemia and of metabolic pathways overall. Furthermore, an integrative view on how glucagon and related signalling pathways can contribute for pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC) progression, since pancreas and liver are the major organs exposed to higher levels of glucagon, pancreas as a producer and liver as a scavenger. The main objective is to bring to discussion some glucagon-dependent mechanisms by presenting an integrative view on microenvironmental and systemic aspects in pNETs and HCC biology.
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Affiliation(s)
- Bárbara Ferreira
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal
| | - Adrián Heredia
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal; Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz MB, 1649-028, Lisboa, Portugal
| | - Jacinta Serpa
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo Dos Mártires da Pátria, 130, 1169-056, Lisboa, Portugal; Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023, Lisboa, Portugal.
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Chang J, Xin C, Wang Y, Wang Y. Dihydroartemisinin inhibits liver cancer cell migration and invasion by reducing ATP synthase production through CaMKK2/NCLX. Oncol Lett 2023; 26:540. [PMID: 38020296 PMCID: PMC10660190 DOI: 10.3892/ol.2023.14127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 09/08/2023] [Indexed: 12/01/2023] Open
Abstract
Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and mitochondrial sodium/calcium exchanger protein (NCLX) are key regulatory factors in calcium homeostasis. Finding natural drugs that target regulators of calcium homeostasis is critical. Dihydroartemisinin (DHA) is considered to have anticancer effects. The present study aimed to investigate the mechanism of DHA in regulating liver cancer migration and invasion. The present study used HepG2 and HuH-7 cells and overexpressed CaMKK2 and knocked down CaMKK2 and NCLX. The antiproliferative activity of DHA on liver cancer cells was assessed through colony formation and EdU assays. Cell apoptosis was detected through YO-PRO-1/PI staining. The levels of reactive oxygen species (ROS) were measured using a ROS detection kit (DCFH-DA fluorescent probe). Cell migratory and invasive abilities were examined using wound healing and Transwell assays. The ATP production of liver cancer cells was detected using ATP fluorescent probes. Cell microfilaments were monitored for changes using Actin-Tracker Green-488. The effects of DHA on the expression of CaMKK2, NCLX, sodium/potassium-transporting ATPase subunit α-1 (ATP1A1) and ATP synthase subunit d, mitochondrial (ATP5H) were determined by western blotting and reverse transcription-quantitative PCR. The results revealed that DHA significantly inhibited proliferation, reduced ROS levels and promoted apoptosis in liver cancer cells. CaMKK2 overexpression significantly enhanced the invasive and migratory ability of liver cancer cells, whereas DHA inhibited the pro-migratory effects of CaMKK2 overexpression. DHA significantly reduced the mitochondrial ATP production and altered the arrangement of microfilaments in liver cancer cells. In addition, DHA significantly decreased the expression of CaMKK2, NCLX, ATP1A1 and ATP5H. Furthermore, by knockdown experiments of NCLX the results demonstrated that CaMKK2 downregulated the expression of ATP1A1 and ATP5H in liver cancer cells through NCLX. In conclusion, DHA may reduce ATP synthase production via the CaMKK2/NCLX signaling pathway to inhibit the invasive phenotype of liver cancer cells. It is essential to further investigate the effectiveness of DHA in the anticancer mechanism of liver cancer cells.
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Affiliation(s)
- Jiang Chang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Chengyi Xin
- Department of Pharmacy, Bayannur Hospital, Bayannur, Inner Mongolia Autonomous Region 015000, P.R. China
| | - Yong Wang
- Department of Neurosurgery, Hainan West Central Hospital, Danzhou, Hainan 571700, P.R. China
| | - Ying Wang
- Department of General Practice, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
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