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1
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Lu XF, Zhang HW, Chang X, Guo YZ. F-box protein 22: A prognostic biomarker for colon cancer associated with immune infiltration and chemotherapy resistance. World J Gastrointest Oncol 2025; 17:102913. [DOI: 10.4251/wjgo.v17.i4.102913] [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: 11/28/2024] [Revised: 01/10/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system, characterized by a high incidence rate and substantial disease burden. The F-box protein 22 (FBXO22) plays a role in forming a specific type of ubiquitin ligase subunit, which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer. Nevertheless, the function of FBXO22 in the context of colon cancer remains inadequately elucidated.
AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery.
METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered, along with pertinent clinical data. Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immunohistochemistry. The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues, and the relationship between these expression levels and various pathologic characteristics of patients, such as age, sex, and clinical stage, was analyzed. Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups: A blank control group, a negative control group, and a si-FBXO22 group. FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting. The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2’-deoxyuridine assay, while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays. Various online platforms, including the Timer Immune Estimation Resource, were used to analyze pan-cancer expression, promoter methylation levels, and mutation frequencies of the FBXO22 gene in colon cancer patients. Additionally, the correlation between FBXO22 gene expression, patient prognosis, immune cell infiltration, and the expression of immune molecules in the colon cancer microenvironment was investigated. The relationship between FBXO22 gene expression and chemotherapy resistance, along with the potential mechanisms of action of the FBXO22 gene, were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software.
RESULTS Compared with normal colonic tissues, the FBXO22 gene was highly expressed in colon cancer tissues. Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents. FBXO22 expression suppresses the infiltration of anti-tumor immune cells. In vitro, FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells.
CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.
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Affiliation(s)
- Xiao-Fei Lu
- Department of Clinical Medicine, Hebei University of Engineering, Handan 056002, Hebei Province, China
| | - Hong-Wei Zhang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Xiao Chang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Yong-Ze Guo
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
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Liu W, Hu K, Fu Y, Zhou T, Zhong Q, Wang W, Gui Y, Zhang P, Yao D, Yang X, Zhu W, Liu Z, Luo D, Xiao Y. Identification of methionine metabolism related prognostic model and tumor suppressive functions of BHMT in hepatocellular carcinoma. Sci Rep 2025; 15:9250. [PMID: 40102459 PMCID: PMC11920202 DOI: 10.1038/s41598-025-93650-w] [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: 09/13/2024] [Accepted: 03/07/2025] [Indexed: 03/20/2025] Open
Abstract
Given the resistance to conventional treatments and limitations of immune checkpoint blockade therapy in hepatocellular carcinoma (HCC), it is imperative to explore novel prognostic models and biomarkers. The dependence of cancer cell on exogenous methionine, known as Hoffman effect, is a hallmark of HCC, with numerous studies reporting a strong correlation between methionine metabolism and tumor development. Betaine-homocysteine S-methyltransferase (BHMT), a critical component of methionine metabolism pathway, has polymorphisms linking to poor prognosis in multiple cancers. Nevertheless, there is little literature regarding the relationship between methionine metabolism and incidence, mortality of HCC, as well as the function of BHMT in HCC progression. In this study, by analyzing multiple datasets, we constructed a methionine metabolism-related prognostic model and thoroughly investigated the influence of BHMT on the prognosis of HCC. Bioinformatics analysis revealed a marked decrease in BHMT expression in HCC, which was linked to adverse clinical outcomes. CIBERSORT results suggest that BHMT promotes infiltration of M1 macrophages. Our results suggest its potential as an ideal prognostic biomarker for anti PD-L1 immunotherapy. In summary, this study innovatively provides first methionine metabolism-related prognostic model and unveils the tumor suppressive function of BHMT in HCC, providing potential mechanism by which BHMT exert its function.
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Affiliation(s)
- Wenli Liu
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Kaiheng Hu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yaqing Fu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Tianmin Zhou
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Qingmei Zhong
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Wu Wang
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Yang Gui
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Ping Zhang
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Di Yao
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Xiaohong Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Weifeng Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Zhuoqi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Daya Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Yingqun Xiao
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China.
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Su W, Zhou Y, Li X, Kang K, Nie H. Construction and Validation of a Novel Butyrylation-Related Gene Signature Related to Prognosis, Clinical Implications, and Immune Microenvironment Characterization of Hepatocellular Carcinoma. ACS OMEGA 2025; 10:3375-3388. [PMID: 39926543 PMCID: PMC11800009 DOI: 10.1021/acsomega.4c06496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 12/26/2024] [Accepted: 01/08/2025] [Indexed: 02/11/2025]
Abstract
Hepatocellular carcinoma (HCC) is a common and highly lethal malignant tumor that poses a serious threat to human health. The post-transcriptional modification of proteins known as butyrylation has emerged as a critical factor in tumorigenesis, playing a pivotal role in the initiation and progression of cancer. This study aimed to develop a prognostic risk model for HCC using butyrylation-related genes (BRGs). Differentially expressed BRGs were identified from the LIHC-TCGA data sets, and a prognostic risk model was constructed using LASSO and multivariate regression analysis. The model's robustness was further confirmed in the GSE14520 cohort. The clinicopathological characteristics, immune features, enrichment pathways, and antitumor drug sensitivity of the BRG signature were also assessed. Additionally, a nomogram was created to improve the predictive accuracy of the model. A set of 16 BRGs, including MMP1, ACOT7, AGPAT5, FLAD1, PDSS1, HSPD1, FKBP1A, AKR1B10, HDAC1, HDAC2, MAPT, ACADS, ACAT1, ACSL6, PDE2A, and PON1, were identified. Kaplan-Meier survival analysis showed that patients in the high-risk group had worse overall survival (OS) and progression-free survival (PFS) compared with those in the low-risk group. Univariate and multivariate Cox regressions, along with LASSO analysis, consistently indicated that the BRG signature is an independent prognostic factor for HCC. Clinical line plots accurately predicted 1, 3, and 5 year survival with AUC values of 0.805, 0.729, and 0.710, respectively. Additionally, the distribution of immune cells varied between different risk groups, and the low-risk group showed more potential for immunotherapy and chemotherapy. This study provides a novel biological basis for prognostic prediction in HCC and offers insights into personalized treatment strategies, including candidate drug selection, for clinicians to guide therapeutic decisions.
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Affiliation(s)
- Weiping Su
- Department
of Orthopedics, The Third Xiangya Hospital,
Central South University, Changsha 410013, China
- Department
of Orthopaedics, The Second Xiangya Hospital
of Central South University, Changsha 410013, China
| | - Yangying Zhou
- Department
of Oncology, Xiangya Hospital, Central South
University, Changsha 410008, China
- National
Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xuanxuan Li
- Department
of Oncology, Xiangya Hospital, Central South
University, Changsha 410008, China
- National
Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Kuo Kang
- Department
of General Surgery, Xiangya Hospital, Central
South University, Changsha 410008, China
- Hunan
Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal
Tumor, Xiangya Hospital, Central South University, Changsha 410008, China
- National
Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Hui Nie
- Department
of Pathology, Xiangya Hospital, Central
South University, Changsha 410008, China
- National
Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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Hu Y, Xiao Y. Mechanism of atorvastatin in treating hepatocellular carcinoma: a study based on network pharmacology, molecular docking, and bioinformatics analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024:10.1007/s00210-024-03598-3. [PMID: 39607545 DOI: 10.1007/s00210-024-03598-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
Hepatocellular carcinoma (HCC) is a tumor with high morbidity and mortality. Current research suggests that statins may aid in its prevention and treatment, while studies on the associated mechanisms remain limited. Therefore, we aim to reveal the mechanism of atorvastatin treatment for HCC by using network pharmacology and bioinformatics methods. The databases SwissTargetPrediction, PharmMapper, and DrugBank were utilized to obtain targets of atorvastatin, while GSE169289, GSE135631, and GSE207435 were used to identify differentially expressed genes (DEGs) for HCC. The overlap between the two groups was used to identify atorvastatin's target for treating HCC. Following protein-protein interaction (PPI) analysis, hub genes were identified using Cytoscape software and LASSO analysis. The hub genes were further validated using data from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) databases. To evaluate the clinical significance of the hub genes, Kaplan-Meier (KM) survival analysis and Cox analysis were conducted. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to investigate potential mechanisms. Finally, molecular docking analysis was performed to validate the interaction between atorvastatin and the hub genes. A total of 1948 DEGs of HCC and 380 targets of atorvastatin were identified, respectively. After taking the intersection, 79 genes were identified as potential targets of atorvastatin for HCC treatment. After multiple screening methods, CYP2C9 was ultimately identified as the hub gene. Analysis of data from TCGA and HPA databases showed reduced expression of CYP2C9 in HCC tissues. KM and Cox analysis showed a favorable prognosis for HCC patients with high CYP2C9 expression. KEGG and GSEA indicated that metabolism of xenobiotics by cytochrome P450, and PPAR signaling pathway could be the potential mechanisms for atorvastatin in treating HCC. Molecular docking analysis revealed that atorvastatin binds to CYP2C9 with a binding energy of - 8.837, indicating highly stable binding. CYP2C9 is associated with the prognosis of HCC patients and could serve as a potential target for atorvastatin treatment in HCC.
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Affiliation(s)
- Youwen Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yangyang Xiao
- Department of Gerontology, Jiangxi University of Traditional Chinese Medicine Affiliated Hospital, No 445, Bayi Avenue, Nanchang, 330006, Jiangxi Province, China.
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Mai Y, Ji Z, Tan Y, Feng L, Qin J. BIRC5 knockdown ameliorates hepatocellular carcinoma progression via regulating PPARγ pathway and cuproptosis. Discov Oncol 2024; 15:706. [PMID: 39585552 PMCID: PMC11589110 DOI: 10.1007/s12672-024-01592-y] [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: 02/21/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) with complex molecular carcinogenesis represents a kind of prevalent neoplasm occurring in the liver. The objective of this study is to illustrate the function of baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) and underlying action mechanisms in HCC progression. METHODS Comprehensive bioinformatics methods were conducted to screen differentially expressed genes (DEGs), cuproptosis-associated DEGs, and hub genes. The correlation between BIRC5 and immune cell infiltration, prognosis value was evaluated. The specific effects of BIRC5 silencing on HCC cells was validated by functional assays, and the impact on tumorigenicity and cuproptosis was also elucidated in vivo. Additionally, the effects of BIRC5 deficiency on PPAR pathway were determined using Oroxin A in vitro. RESULTS A total of 45 cuproptosis-associated DEGs and 9 hub genes were discovered through bioinformatics. Then 6 core genes were confirmed in Hep-3B and SK-Hep-1 cells with 4 genes upregulated and 2 genes downregulated. Therein, BIRC5 was positively correlated with the infiltration of CD8+ T cells, macrophages, and highly expressed BIRC5 exhibited poor prognosis of overall survival in HCC. Furthermore, BIRC5 deletion inhibited the PPARγ pathway, thereby restraining the malignant phenotypes of HCC cells and tumorigenesis in vivo. Additionally, silencing of BIRC5 contributed to the initiation of cuproptosis in HCC. CONCLUSIONS BIRC5 silencing attenuated HCC through blocking PPARγ pathway and regulating cuproptosis, which may offer therapeutic implications against HCC.
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Affiliation(s)
- Yanxing Mai
- Department of Geriatrics, Guangdong, Zhujiang Hospital of Southern Medical University, No. 253 Gongye Avenue, Guangzhou, 510282, China
| | - Zhuocheng Ji
- Second Department of Hepatobiliary Surgery, Guangdong, Zhujiang Hospital of Southern Medical University, No. 253 Gongye Avenue, Haizhu District, Guangzhou, 510282, China
| | - Yujing Tan
- Department of Radiotherapy, Guangdong, Zhujiang Hospital of Southern Medical University, No. 253 Gongye Avenue, Guangzhou, 510282, China
| | - Lei Feng
- Department of Hepatobiliary Surgery, Guizhou, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550000, China
| | - Jiasheng Qin
- Second Department of Hepatobiliary Surgery, Guangdong, Zhujiang Hospital of Southern Medical University, No. 253 Gongye Avenue, Haizhu District, Guangzhou, 510282, China.
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6
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Yang L, Li L, Li P, Chen J, Cai C, Jia Y, Li J, Zou B. Higher Expression of Ku80 and Ku70 Indicates Hotter Tumor Immune Microenvironment in Hepatocellular Carcinoma and Better CTL-Centered Immunotherapy. J Inflamm Res 2024; 17:9511-9525. [PMID: 39600673 PMCID: PMC11590648 DOI: 10.2147/jir.s496123] [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: 09/13/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
Purpose Both Ku80 and Ku70 are promising drug targets for hepatocellular carcinoma (HCC) and crucial for immune regulation. However, their correlation with HCC immune signatures has not yet been investigated. Therefore, we aimed to investigate the relationship between Ku80, Ku70, and immune signatures in HCC and validate their significance in cytotoxic lymphocyte (CTL) immunotherapy. Patients and Methods Analyses of Ku70, Ku80, and immune signatures in public datasets was performed using R software, an online Kaplan-Meier plotter, g:Profiler, GeneTrail, and Metascape. Uniform manifold approximation and projection, correlation chord diagrams, Pearson's correlation tests, and Spearman correlation tests were used to describe various correlation levels. HCC mRNA sequencing data (n=373 tumor samples and n=50 para-tumor samples) were drawn from The Cancer Genome Atlas (TCGA) public database. Immunofluorescent staining was used to validate Ku70/Ku80 and CD8+CTL expression in 120 HCC patients from our center. Survival analysis was performed using the Kaplan-Meier survival analysis with the Log rank test and was adopted to analyze immunotherapy outcomes correlated with Ku70/Ku80 expression in various solid tumors. Multivariate analysis of HCC patient data from our center was performed using a Cox proportional hazards model. Results Increased Ku70/Ku80 expression positively correlated with more enriched immune microenvironment signatures, indicating increased immune infiltration in HCC. Upregulation of Ku70/Ku80 indicated better anti-PD1 and anti-PDL1 treatment outcomes in various solid tumors. Higher Ku70/Ku80 expression with lower CD8+CTL signatures indicated worse survival outcomes, whereas lower Ku70/Ku80 expression with higher CD8+CTL signatures indicated the best prognosis. Conclusion Higher Ku70/Ku80 expression indicated an immune-hot infiltration signature in HCC. Patients with increased Ku70/Ku80 expression and high CD8+CTL signatures may potentially benefit from CTL-centered immunotherapies.
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Affiliation(s)
- Lukun Yang
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
- Department of Anesthesiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Ling Li
- Department of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China
| | - Peiping Li
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Jiafan Chen
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Chaonong Cai
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Yingbin Jia
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Jian Li
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
| | - Baojia Zou
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People’s Republic of China
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Li W, Chen G, Peng H, Zhang Q, Nie D, Guo T, Zhu Y, Zhang Y, Lin M. Research Progress on Dendritic Cells in Hepatocellular Carcinoma Immune Microenvironments. Biomolecules 2024; 14:1161. [PMID: 39334927 PMCID: PMC11430656 DOI: 10.3390/biom14091161] [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: 07/17/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated DCs present these antigens to naive T cells, thereby stimulating T cell-mediated immune responses and enhancing their ability to attack tumors. It is particularly noted that DCs are able to cross-present foreign antigens to major histocompatibility complex class I (MHC-I) molecules, prompting CD8+ T cells to proliferate and differentiate into cytotoxic T cells. In the malignant progression of hepatocellular carcinoma (HCC), the inactivation of DCs plays an important role, and the activation of DCs is particularly important in anti-HCC immunotherapy. In this review, we summarize the mechanisms of DCs activation in HCC, the involved regulatory factors and strategies to activate DCs in HCC immunotherapy. It provides a basis for the study of HCC immunotherapy through DCs activation.
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Affiliation(s)
- Wenya Li
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Guojie Chen
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Medical School, Nantong University, Nantong 226019, China
| | - Hailin Peng
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Qingfang Zhang
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Dengyun Nie
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ting Guo
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yinxing Zhu
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Yuhan Zhang
- The First School of Clinical Medicine Southern Medical University, Guangzhou 510515, China
| | - Mei Lin
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Shan L, Chen Y, An G, Tao X, Qiao C, Chen M, Li J, Lin R, Wu J, Zhao C. Polyphyllin I exerts anti-hepatocellular carcinoma activity by targeting ZBTB16 to activate the PPARγ/RXRα signaling pathway. Chin Med 2024; 19:113. [PMID: 39182119 PMCID: PMC11344421 DOI: 10.1186/s13020-024-00984-0] [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: 06/04/2024] [Accepted: 08/13/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC. METHODS Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study. RESULTS The results demonstrated that PPI had significant anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC. CONCLUSIONS Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis.
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Affiliation(s)
- Lu Shan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Yijun Chen
- Institute of Prescriptions and Syndromes, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Guo An
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaoyu Tao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chuanqi Qiao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Meilin Chen
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
- Department of Pharmacy, Jinjiang Municipal Hospital, Quanzhou, 362200, Fujian, China
| | - Jiaqi Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Ruichao Lin
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Chongjun Zhao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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Moral-Turón C, Asencio-Cortés G, Rodriguez-Diaz F, Rubio A, Navarro AG, Brokate-Llanos AM, Garzón A, Muñoz MJ, Pérez-Pulido AJ. ASACO: Automatic and Serial Analysis of CO-expression to discover gene modifiers with potential use in drug repurposing. Brief Funct Genomics 2024; 23:484-494. [PMID: 38422352 DOI: 10.1093/bfgp/elae006] [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: 09/07/2023] [Revised: 01/21/2024] [Accepted: 01/31/2024] [Indexed: 03/02/2024] Open
Abstract
Massive gene expression analyses are widely used to find differentially expressed genes under specific conditions. The results of these experiments are often available in public databases that are undergoing a growth similar to that of molecular sequence databases in the past. This now allows novel secondary computational tools to emerge that use such information to gain new knowledge. If several genes have a similar expression profile across heterogeneous transcriptomics experiments, they could be functionally related. These associations are usually useful for the annotation of uncharacterized genes. In addition, the search for genes with opposite expression profiles is useful for finding negative regulators and proposing inhibitory compounds in drug repurposing projects. Here we present a new web application, Automatic and Serial Analysis of CO-expression (ASACO), which has the potential to discover positive and negative correlator genes to a given query gene, based on thousands of public transcriptomics experiments. In addition, examples of use are presented, comparing with previous contrasted knowledge. The results obtained propose ASACO as a useful tool to improve knowledge about genes associated with human diseases and noncoding genes. ASACO is available at http://www.bioinfocabd.upo.es/asaco/.
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Affiliation(s)
- Cristina Moral-Turón
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | | | | | - Alejandro Rubio
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | - Alberto G Navarro
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | - Ana M Brokate-Llanos
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | - Andrés Garzón
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | - Manuel J Muñoz
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
| | - Antonio J Pérez-Pulido
- Andalusian Centre for Developmental Biology (CABD, UPO-CSIC-JA). Faculty of Experimental Sciences (Genetics Dept.), University Pablo de Olavide, 41013, Seville, Spain
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10
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Singal AK, Shah VH, Malhi H. Emerging targets for therapy in ALD: Lessons from NASH. Hepatology 2024; 80:223-237. [PMID: 36938877 PMCID: PMC10511666 DOI: 10.1097/hep.0000000000000381] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 03/09/2023] [Indexed: 03/21/2023]
Abstract
Alcohol-associated liver disease due to harmful alcohol use and NAFLD associated with metabolic syndrome are the 2 most common liver diseases worldwide. Control of respective risk factors is the cornerstone in the long-term management of these diseases. Furthermore, there are no effective therapies. Both diseases are characterized by metabolic derangements; thus, the focus of this review was to broaden our understanding of metabolic targets investigated in NAFLD, and how these can be applied to alcohol-associated liver disease. Conserved pathogenic pathways such as dysregulated lipid metabolism, cell death pathways including apoptosis and activation of innate immune cells, and stellate cells mediate both alcohol and NAFLDs, resulting in histological abnormalities of steatosis, inflammation, fibrosis, and cirrhosis. However, pathways such as gut microbiome changes, glucose metabolism and insulin resistance, inflammatory signaling, and microRNA abnormalities are distinct in these 2 diseases. In this review article, we describe conserved and distinct pathogenic pathways highlighting therapeutic targets that may be of potential in both diseases and those that are unique to each disease.
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Affiliation(s)
- Ashwani K. Singal
- Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA
- Division of Gastroenterology and Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota, USA
- VA Medical Center, Sioux Falls, South Dakota, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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11
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Mao X, Wu S, Huang D, Li C. Complications and comorbidities associated with antineoplastic chemotherapy: Rethinking drug design and delivery for anticancer therapy. Acta Pharm Sin B 2024; 14:2901-2926. [PMID: 39027258 PMCID: PMC11252465 DOI: 10.1016/j.apsb.2024.03.006] [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: 11/26/2023] [Revised: 01/29/2024] [Accepted: 02/10/2024] [Indexed: 07/20/2024] Open
Abstract
Despite the considerable advancements in chemotherapy as a cornerstone modality in cancer treatment, the prevalence of complications and pre-existing diseases is on the rise among cancer patients along with prolonged survival and aging population. The relationships between these disorders and cancer are intricate, bearing significant influence on the survival and quality of life of individuals with cancer and presenting challenges for the prognosis and outcomes of malignancies. Herein, we review the prevailing complications and comorbidities that often accompany chemotherapy and summarize the lessons to learn from inadequate research and management of this scenario, with an emphasis on possible strategies for reducing potential complications and alleviating comorbidities, as well as an overview of current preclinical cancer models and practical advice for establishing bio-faithful preclinical models in such complex context.
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Affiliation(s)
- Xiaoman Mao
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Shuang Wu
- Medical Research Institute, Southwest University, Chongqing 400715, China
| | - Dandan Huang
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Chong Li
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
- Medical Research Institute, Southwest University, Chongqing 400715, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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12
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Lan T, Li P, Zhang SJ, Liu SY, Zeng XX, Chai F, Tong YH, Mao ZJ, Wang SW. Paeoniflorin promotes PPARγ expression to suppress HSCs activation by inhibiting EZH2-mediated histone H3K27 trimethylation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155477. [PMID: 38489890 DOI: 10.1016/j.phymed.2024.155477] [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: 10/02/2023] [Revised: 02/20/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND The alleviating effect of paeoniflorin (Pae) on liver fibrosis has been established; however, the molecular mechanism and specific target(s) underlying this effect remain elusive. PURPOSE This study was to investigate the molecular mechanism underlying the regulatory effect of Pae on hepatic stellate cells (HSCs) activation in liver fibrosis, with a specific focus on the role of Pae in modulating histone methylation modifications. METHODS The therapeutic effect of Pae was evaluated by establishing in vivo and in vitro models of carbon tetrachloride (CCl4)-induced mice and transforming growth factor β1 (TGF-β1)-induced LX-2 cells, respectively. Molecular docking, surface plasmon resonance (SPR), chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and other molecular biological methods were used to clarify the molecular mechanism of Pae regulating HSCs activation. RESULTS Our study found that Pae inhibited HSCs activation and histone trimethylation modification in liver of CCl4-induced mice and LX-2 cells. We demonstrated that the inhibitory effect of Pae on the activation of HSCs was dependent on peroxisome proliferator-activated receptor γ (PPARγ) expression and enhancer of zeste homolog 2 (EZH2). Mechanistically, Pae directly binded to EZH2 to effectively suppress its enzymatic activity. This attenuation leaded to the suppression of histone H3K27 trimethylation in the PPARγ promoter region, which induced upregulation of PPARγ expression. CONCLUSION This investigative not only sheds new light on the precise targets that underlie the remission of hepatic fibrogenesis induced by Pae but also emphasizes the critical significance of EZH2-mediated H3K27 trimethylation in driving the pathogenesis of liver fibrosis.
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Affiliation(s)
- Tian Lan
- Laboratory Animal Resources Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 100 Minjiang Road, Quzhou 324000, China; Panvascular Diseases Research Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
| | - Ping Li
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Si-Jia Zhang
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Shi-Yu Liu
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China
| | - Xi-Xi Zeng
- Panvascular Diseases Research Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China
| | - Fang Chai
- Department of Orthopedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Yu-Hua Tong
- Panvascular Diseases Research Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China; Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China
| | - Zhu-Jun Mao
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou 310053, China; Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
| | - Si-Wei Wang
- Laboratory Animal Resources Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 100 Minjiang Road, Quzhou 324000, China; Panvascular Diseases Research Center, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou 324000, China.
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Du S, Chen X, Ren R, Li L, Zhang B, Wang Q, Meng Y, Qiu Z, Wang G, Zheng G, Hu J. Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the amelioration of AKT-induced nonalcoholic fatty liver disease by total flavonoids in vine tea. Food Funct 2024; 15:5158-5174. [PMID: 38630029 DOI: 10.1039/d4fo00586d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the main reason for chronic liver diseases and malignancies. Currently, there is a lack of approved drugs for the prevention or treatment of NAFLD. Vine tea (Ampelopsis grossedentata) has been used as a traditional Chinese beverage for centuries. Vine tea carries out several biological activities including the regulation of plasma lipids and blood glucose, hepato-protective function, and anti-tumor activity and contains the highest content of flavonoids. However, the underlying mechanisms of total flavonoids from vine tea (TF) in the attenuation of NAFLD remain unclear. Therefore, we investigated the interventions and mechanisms of TF in mice with NAFLD using an integrated analysis of network pharmacology, lipidomics, and transcriptomics. Staining and biochemical tests revealed a significant increase in AKT-overexpression-induced (abbreviated as AKT-induced) NAFLD in mice. Lipid accumulation in hepatic intracellular vacuoles was alleviated after TF treatment. In addition, TF reduced the hepatic and serum triglyceride levels in mice with AKT-induced NAFLD. Lipidomics results showed 32 differential lipids in the liver, mainly including triglycerides (TG), diglycerides (DG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). Transcriptomic analysis revealed that 314 differentially expressed genes were commonly upregulated in the AKT group and downregulated in the TF group. The differential regulation of lipids by the genes Pparg, Scd1, Chpt1, Dgkz, and Pla2g12b was further revealed by network enrichment analysis and confirmed by RT-qPCR. Furthermore, we used immunohistochemistry (IHC) to detect changes in the protein levels of the key proteins PPARγ and SCD1. In summary, TF can improve hepatic steatosis by targeting the PPAR signaling pathway, thereby reducing de novo fatty acid synthesis and modulating the glycerophospholipid metabolism.
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Affiliation(s)
- Siyu Du
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Xin Chen
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Rumeng Ren
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Li Li
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
| | - Baohui Zhang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Qi Wang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Yan Meng
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Guihong Wang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
| | - Guohua Zheng
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
| | - Junjie Hu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
- Center of Traditional Chinese Medicine Modernization for Liver Diseases, Hubei University of Chinese Medicine, Wuhan, People's Republic of China
- Hubei Shizhen Laboratory, Wuhan, People's Republic of China
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Yang Y, He Z, Wu S. Ursolic acid alleviates paclitaxel-induced peripheral neuropathy through PPARγ activation. Toxicol Appl Pharmacol 2024; 484:116883. [PMID: 38437959 DOI: 10.1016/j.taap.2024.116883] [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: 12/03/2023] [Revised: 02/10/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) reduces the overall quality of life and leads to interruption of chemotherapy. Ursolic acid, a triterpenoid naturally which presents in fruit peels and in many herbs and spices, can function as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and has been widely used as an herbal medicine with a wide spectrum of pharmacological activities, including anti-cancer, anti-inflammatory and neuroprotective effect. METHODS We used a phenotypic drug screening approach to identify ursolic acid as a potential neuroprotective drug in vitro and in vivo and carried out additional biochemical experiments to identify its mechanism of action. RESULTS Our study demonstrated that ursolic acid reduced neurotoxicity and cell apoptosis induced by pacilitaxel, resulting in an improvement of CIPN. Moreover, we explored the potential mechanisms of ursolic acid on CIPN. As a result, ursolic acid inhibited CHOP (C/EBP Homologous Protein) expression, indicating the endoplasmic reticulum (ER) stress suppression, and regulating CHOP related apoptosis regulator (the Bcl2 family) to reverse pacilitaxel induced apoptosis. Moreover, we showed that the therapeutic effect of ursolic acid on the pacilitaxel-induced peripheral neuropathy is PPARγ dependent. CONCLUSIONS Taken together, the present study suggests ursolic acid has potential as a new PPARγ agonist targeting ER stress-related apoptotic pathways to ameliorate pacilitaxel-induced peripheral neuropathic pain and nerve injury, providing new clinical therapeutic method for CIPN.
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Affiliation(s)
- Yulian Yang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Shaanxi 710072, China
| | - Zhongzheng He
- Department of Neurosurgery, Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, Shaanxi 710003, China
| | - Shuangchan Wu
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Shaanxi 710072, China; Research & Development Institute of Northwestern Polytechnical University, Shenzhen, Guangdong 518057, China.
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15
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Zhao Y, Tan H, Zhang X, Zhu J. Roles of peroxisome proliferator-activated receptors in hepatocellular carcinoma. J Cell Mol Med 2024; 28:e18042. [PMID: 37987033 PMCID: PMC10902579 DOI: 10.1111/jcmm.18042] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.
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Affiliation(s)
- Yaqin Zhao
- Department of Abdominal Oncology, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin HospitalHubei University of MedicineShiyanHubeiChina
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General SurgeryThe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'anChina
| | - Jing Zhu
- Nanjing Drum Tower HospitalNanjingChina
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Shi Q, Zeng Y, Xue C, Chu Q, Yuan X, Li L. Development of a promising PPAR signaling pathway-related prognostic prediction model for hepatocellular carcinoma. Sci Rep 2024; 14:4926. [PMID: 38418897 PMCID: PMC10902383 DOI: 10.1038/s41598-024-55086-6] [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: 08/27/2023] [Accepted: 02/20/2024] [Indexed: 03/02/2024] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) signaling pathway plays a crucial role in systemic cell metabolism, energy homeostasis and immune response inhibition. However, its significance in hepatocellular carcinoma (HCC) has not been well documented. In our study, based on the RNA sequencing data of HCC, consensus clustering analyses were performed to identify PPAR signaling pathway-related molecular subtypes, each of which displaying varying survival probabilities and immune infiltration status. Following, a prognostic prediction model of HCC was developed by using the random survival forest method and Cox regression analysis. Significant difference in survival outcome, immune landscape, drug sensitivity and pathological features were observed between patients with different prognosis. Additionally, decision tree and nomogram models were adopted to optimize the prognostic prediction model. Furthermore, the robustness of the model was verified through single-cell RNA-sequencing data. Collectively, this study systematically elucidated that the PPAR signaling pathway-related prognostic model has good predictive efficacy for patients with HCC. These findings provide valuable insights for further research on personalized treatment approaches for HCC.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
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17
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Shi Z, Zhu S, Jin Y, Qi L, Zhou M, Zhou Z, Zhang J, Liu B, Shen J. Lymphocyte-to-C Reactive Protein Ratio is an Independent Predictor of Survival Benefits for Hepatocellular Carcinoma Patients Receiving Radiotherapy. J Hepatocell Carcinoma 2024; 11:305-316. [PMID: 38348098 PMCID: PMC10860807 DOI: 10.2147/jhc.s452424] [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: 11/29/2023] [Accepted: 01/23/2024] [Indexed: 02/15/2024] Open
Abstract
Background Stereotactic body radiotherapy (SBRT) has emerged as an alternative approach for patients with hepatocellular carcinoma (HCC), and we aim to find potential prognostic biomarkers for HCC patients who received SBRT. Methods In this study, we retrospectively analyzed HCC patients who underwent SBRT in our institution from January 2018 to December 2022. The inflammatory parameters, along with baseline patients' characteristics were collected to elucidate the potential relationship with survival benefits and liver toxicities. Results Overall, 35 patients were enrolled in our study. For the efficacy population (25 patients who underwent SBRT for primary liver lesions), the objective response rate (ORR) and disease control rate (DCR) were 60% and 100%, respectively. The median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI) 5.6-14.1 months], and the median overall survival (OS) was 18.5 months (95% CI 14.2-22.8 months). We further confirmed that higher baseline lymphocyte-C-reactive protein ratio (LCR) (≥2361.11) was positively related to both longer PFS (12.0 vs 4.3 months, P = 0.002) and OS (21.9 vs 11.4 months, P = 0.022). Moreover, patients with diabetes and higher alpha-fetoprotein (AFP) (≥400 ng/mL) were also found to be associated with worse OS. The most common hepatotoxicity was elevated gamma-glutamyl transferase (GGT) (84.0%). Conclusion In conclusion, for patients with inoperable HCC, SBRT resulted in satisfactory local control, survival benefits, and acceptable liver toxicity. Pre-radiotherapy LCR might be an independent and readily available predictor for survival, which facilitates us to find the most appropriate treatment options.
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Affiliation(s)
- Zhan Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Sihui Zhu
- The Comprehensive Cancer Centre of Nanjing International Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Yuncheng Jin
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Liang Qi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Mingzhen Zhou
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Ziyan Zhou
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Juan Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
| | - Jie Shen
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu Province, 210008, People’s Republic of China
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Wu Q, Wang P, Peng Q, Kang Z, Deng Y, Li J, Chen Y, Li J, Ge F. Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker. Int J Mol Sci 2023; 24:16986. [PMID: 38069309 PMCID: PMC10707058 DOI: 10.3390/ijms242316986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Adhesion G protein-coupled receptor G2 (ADGRG2) is an orphan adhesion G protein-coupled receptor (GPCR), which performs a tumor-promoting role in certain cancers; however, it has not been systematically investigated in hepatocellular carcinoma (HCC). In the current study, we utilized multiple databases to analyze the expression and diagnostic and prognostic value of ADGRG2 in HCC and its correlation with immune infiltration and inflammatory factors. The function and upstream regulatory miRNA of ADGRG2 were validated through qPCR, Western blot, CCK8, wound healing, and dual luciferase assays. It turned out that ADGRG2 was significantly higher in HCC and had a poor survival rate, especially in AFP ≤ 400 ng/mL subgroups. Functional enrichment analysis suggested that ADGRG2 may be involved in cancer pathways and immune-related pathways. In vitro, siRNA-mediated ADGRG2 silencing could inhibit the proliferation and migration of Huh7 and HepG2 cells. There was a highly significant positive correlation between ADGRG2 and neutrophils. Moreover, NET-related genes were filtered and confirmed, such as ENO1 and S100A9. Meanwhile, the high expression of ADGRG2 was also accompanied by the highest number of inflammatory cytokines, chemokines, and chemokine receptors and good immunotherapy efficacy. Finally, AGDGR2 may be sensitive to two drugs (PIK-93 and NPK76-II-72-1) and can be targeted by miR-326. In conclusion, ADGRG2 may serve as a novel biomarker and drug target for HCC diagnosis, immunotherapy, and prognosis and was related to neutrophils and the inflammatory process of liver cancer development.
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Affiliation(s)
- Qian Wu
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Pei Wang
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Qihang Peng
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Zhongcui Kang
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Yiting Deng
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Jiayi Li
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Ying Chen
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Jin Li
- College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Feng Ge
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
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Tian L, Wang Y, Zhang Z, Feng X, Xiao F, Zong M. CD72, a new immune checkpoint molecule, is a novel prognostic biomarker for kidney renal clear cell carcinoma. Eur J Med Res 2023; 28:531. [PMID: 37980541 PMCID: PMC10656955 DOI: 10.1186/s40001-023-01487-8] [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: 09/20/2023] [Accepted: 10/30/2023] [Indexed: 11/20/2023] Open
Abstract
BACKGROUND The incidence and mortality of clear cell carcinoma of the kidney increases yearly. There are limited screening methods and advances in treating kidney renal clear cell carcinoma (KIRC). It is important to find new biomarkers to screen, diagnose and predict the prognosis of KIRC. Some studies have shown that CD72 influences the development and progression of colorectal cancer, nasopharyngeal cancer, and acute lymphoid leukemia. However, there is a lack of research on the role of CD72 in the pathogenesis of KIRC. This study aimed to determine whether CD72 is associated with the prognosis and immune infiltration of KIRC, providing an essential molecular basis for the early non-invasive diagnosis and immunotherapy of KIRC. METHODS Using TCGA, GTE, GEO, and ImmPort databases, we obtained the differentially expressed mRNA (DEmRNA) associated with the prognosis and immunity of KIRC patients. We used the Kruskal-Wallis test to identify clinicopathological parameters associated with target gene expression. We performed univariate and multivariate COX regression analyses to determine the effect of target gene expression and clinicopathological parameters on survival. We analyzed the target genes' relevant functions and signaling pathways through enrichment analysis. Finally, the correlation of target genes with tumor immune infiltration was explored by ssGSEA and Spearman correlation analysis. RESULTS The results revealed that patients with KIRC with higher expression of CD72 have a poorer prognosis. CD72 was associated with the Pathologic T stage, Pathologic stage, Pathologic M stage, Pathologic N stage, Histologic grade in KIRC patients, Laterality, and OS event. It was an independent predictor of the overall survival of KIRC patients. Functional enrichment analysis showed that CD72 was significantly enriched in oncogenic and immune-related pathways. According to ssGSEA and Spearman correlation analysis, CD72 expression was significantly associated with tumor immune cells and immune checkpoints. CONCLUSION Our study suggests that CD72 is associated with tumor immunity and may be a biomarker relevant to the diagnosis and prognosis of KIRC patients.
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Affiliation(s)
- Lv Tian
- Department of Rehabilitation, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
- School of Nursing, Jilin University, Changchun, China
| | - Yiming Wang
- School of Nursing, Jilin University, Changchun, China
| | - Zhiyuan Zhang
- School of Nursing, Jilin University, Changchun, China
| | - Xuechao Feng
- School of Life Sciences, Northeast Normal University, Changchun, China
| | - Fengjun Xiao
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
| | - Minru Zong
- Department of Rehabilitation, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
- School of Nursing, Jilin University, Changchun, China.
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Zhang S, Peng W, Wang H, Xiang X, Ye L, Wei X, Wang Z, Xue Q, Chen L, Su Y, Zhou Q. C1q + tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion. J Immunother Cancer 2023; 11:e007441. [PMID: 37604643 PMCID: PMC10445384 DOI: 10.1136/jitc-2023-007441] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet. METHODS Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q+ TAMs. RESULTS C1q+ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q+ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8+ T cells. Mechanistically, C1q+ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q+ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer. CONCLUSIONS C1q+ TAMs impede antitumor effects of CD8+ T cells promoting MPE immunosuppression. Targeting C1q+ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q+ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.
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Affiliation(s)
- Siyu Zhang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbei Peng
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haolei Wang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Xiang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linlin Ye
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoshan Wei
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihao Wang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qianqian Xue
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Long Chen
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Su
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Zhou
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Arzumanian V, Pyatnitskiy M, Poverennaya E. Comparative Transcriptomic Analysis of Three Common Liver Cell Lines. Int J Mol Sci 2023; 24:ijms24108791. [PMID: 37240140 DOI: 10.3390/ijms24108791] [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: 04/18/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Comparative transcriptomic analysis is a powerful approach for investigating the molecular mechanisms underlying various physiological and pathological processes, including liver disease. The liver is a vital organ with diverse functions, including metabolism and detoxification. In vitro models of liver cells, such as HepG2, Huh7, and Hep3B, have been widely used to study liver biology and pathology. However, there is limited information on the heterogeneity of these cell lines at the transcriptomic level. OBJECTIVE This study aimed to conduct a comparative transcriptomic analysis of three common liver cell lines (HepG2, Huh7, and Hep3B) using publicly available RNA-sequencing data. In addition, we compared these cell lines to primary hepatocytes, cells isolated directly from liver tissue and considered the gold standard for studying liver function and disease. METHODS Our study included sequencing data with the following criteria: total number of reads over 20,000,000, average read length of over 60 base pairs, Illumina sequencing, and non-treated cells. The data for the three cell lines were compiled: HepG2 (97 samples), Huh7 (39 samples), and Hep3B (16 samples). We performed differential gene expression analysis using the DESeq2 package, principal component analysis, hierarchical clustering on principal components, and correlation analysis to explore the heterogeneity within each cell line. RESULTS We identified numerous genes and pathways differentially expressed between HepG2, Huh7, and Hep3B, such as oxidative phosphorylation, cholesterol metabolism, and DNA damage. We report that the expression levels of important genes differ significantly between primary hepatocytes and liver cell lines. CONCLUSION Our study provides new insights into the transcriptional heterogeneity of commonly used liver cell lines and highlights the importance of considering specific cell line. Consequently, transferring results without considering the heterogeneity of cell lines is impractical and may lead to inaccurate or distorted conclusions.
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Targeting tumor-associated macrophages in hepatocellular carcinoma: biology, strategy, and immunotherapy. Cell Death Discov 2023; 9:65. [PMID: 36792608 PMCID: PMC9931715 DOI: 10.1038/s41420-023-01356-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most malignant tumors, is characterized by its stubborn immunosuppressive microenvironment. As one of the main members of the tumor microenvironment (TME) of HCC, tumor-associated macrophages (TAMs) play a critical role in its occurrence and development, including stimulating angiogenesis, enhancing immunosuppression, and promoting the drug resistance and cancer metastasis. This review describes the origin as well as phenotypic heterogeneity of TAMs and their potential effects on the occurrence and development of HCC and also discusses about various adjuvant therapy based strategies that can be used for targeting TAMs. In addition, we have highlighted different treatment modalities for TAMs based on immunotherapy, including small molecular inhibitors, immune checkpoint inhibitors, antibodies, tumor vaccines, adoptive cellular immunotherapy, and nanocarriers for drug delivery, to explore novel combination therapies and provide feasible therapeutic options for clinically improving the prognosis and quality of life of HCC patients.
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