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Xu ZJ, Liu B, Li RN, Linghu H. GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway. Open Life Sci 2025; 20:20221039. [PMID: 40291779 PMCID: PMC12032973 DOI: 10.1515/biol-2022-1039] [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: 09/13/2024] [Revised: 11/27/2024] [Accepted: 12/10/2024] [Indexed: 04/30/2025] Open
Abstract
This study investigated the role of glutamine-fructose-6-phosphate transaminase 2 (GFPT2) in the response of epithelial ovarian cancer cells to paclitaxel, a standard chemotherapy drug. We analyzed GFPT2 expression across various EOC cell lines, including SKOV3, HEY, ES-2, A2780, and OVCR3. In HEY cell lines, we performed GFPT2 knockdown, while A2780 cells were engineered for GFPT2 overexpression. Following these manipulations, we assessed the cellular responses to paclitaxel treatment. Results demonstrated a correlation between GFPT2 levels and paclitaxel resistance; those with high GFPT2 (SKOV3 and HEY) expression were less sensitive compared to the cells with low GFPT2 expression (A2780). Downregulating GFPT2 enhanced drug sensitivity in HEY cells, whereas its overexpression impaired drug sensitivity in A2780 cells. Mechanistically, GFPT2's role in facilitating paclitaxel resistance was linked to the activation of the nuclear factor-κB (NF-κB) signaling pathway, possibly influenced by NK3 Homeobox 2. Our findings suggest that GFPT2 is a critical mediator of paclitaxel resistance through NF-κB pathway activation in EOC, providing potential targets for improving therapeutic efficacy against this challenging malignancy.
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Affiliation(s)
- Zi-Jun Xu
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Bin Liu
- Department of Pathology, The Basic Medical School of Chongqing Medical University, Chongqing, 400016, China
| | - Ruo-Nan Li
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hua Linghu
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
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Su H, Zhong Y, He L, Geng F, Yin X, Kou Y, Chiang CY, Mo X, Fan Y, Liu Y, Wang Q, Magaki S, Cloughesy TF, Lefai E, Yong WH, Chakravarti A, Zhang X, Guo D. Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth. SCIENCE ADVANCES 2025; 11:eadq0334. [PMID: 40249802 PMCID: PMC12007565 DOI: 10.1126/sciadv.adq0334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 03/14/2025] [Indexed: 04/20/2025]
Abstract
Elevated hexosamine biosynthesis fuels tumor growth by facilitating protein and lipid glycosylation. But which enzyme in this pathway is better to serve as an antitumor target remains unclear. Here, we revealed that targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, exhibits limited inhibitory effects on glioblastoma (GBM), the most lethal brain tumor. This outcome is due to the compensation of NAGK-mediated hexosamine salvage pathway. Unexpectedly, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, down-regulates the expression of other enzymes in this pathway and suppresses SREBP-1, a critical lipogenic transcription factor, effectively inhibiting GBM growth. Unexpectedly, SREBP-1 transcriptionally up-regulates the expression of hexosamine synthesis enzymes, while inhibition of these enzymes in turn down-regulates SREBP-1 activation via reducing N-glycosylation of its transporter, SCAP. Our study identified PGM3 as a promising target for treating GBM. Its inhibition disrupts the SREBP-1 activation-hexosamine synthesis positive feedback regulation to effectively eliminate GBM cells.
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Affiliation(s)
- Huali Su
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Yaogang Zhong
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Liqing He
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
| | - Feng Geng
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Xinmin Yin
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
| | - Yongjun Kou
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Cheng-Yao Chiang
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Xiaokui Mo
- Biostatistic Center and Department of Biomedical Informatics, College of Medicine at The Ohio State University, Columbus, OH 43210, USA
| | - Yunzhou Fan
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Yanwei Liu
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Qiang Wang
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Shino Magaki
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Timothy F. Cloughesy
- Department of Neurology (Neuro-Oncology), David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Etienne Lefai
- Université Clermont Auvergne, INRAE, UNH UMR 1019, CRNH Auvergne, 63000 Clermont-Ferrand, France
| | - William H Yong
- Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA
| | - Arnab Chakravarti
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
| | - Xiang Zhang
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
| | - Deliang Guo
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
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Chen L, Wang X, Li J, Zhang L, Wu W, Wei S, Zou W, Zhao Y. Elucidation of the mechanism of berberine against gastric mucosa injury in a rat model with chronic atrophic gastritis based on a combined strategy of multi-omics and molecular biology. Front Pharmacol 2025; 15:1499753. [PMID: 39834822 PMCID: PMC11743660 DOI: 10.3389/fphar.2024.1499753] [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: 09/21/2024] [Accepted: 12/13/2024] [Indexed: 01/22/2025] Open
Abstract
Background Berberine (BBR) is widely used to treat gastrointestinal diseases. However, the pharmacological mechanism of action of BBR in anti-chronic atrophic gastritis (CAG) remains unclear. This study aimed to investigate the mechanism of action of BBR in CAG by integration of molecular biology and multi-omics studies strategy. Methods The CAG model was established by alternating drinking water of 0.1% ammonia and 20 mmol/L sodium deoxycholate, accompanied by an irregular diet. Serum biochemical indices including PGI, PGII, GAS-17, IL-6, IL-1β, and TNF-α were analyzed. HE and AB-PAS staining were employed to assess pathological damage in gastric tissue. The underlying molecular mechanism of BBR in CAG treatment was explored via the integration of network pharmacology, transcriptomics, widely targeted metabolomics and intestinal flora analysis. Finally, relevant key targets and pathway were verified. Results The results showed that BBR exerted therapeutic effects in improving CAG via alleviating inflammation response, maintaining the gastric mucosal barrier's integrity and repairing gastric mucosal tissues. Network pharmacology showed that the treatment of CAG by BBR mainly involved in inflammatory response, apoptosis, angiogenesis and metabolic processes. Furthermore, 234 different expression genes were identified in the gastric tissue transcriptome, which were mainly involved in biological processes such as cell adhesion, angiogenesis, apoptosis, cell migration and lipids metabolism by regulating the MAPK signaling pathway. Metabolomics results showed that 125 differential metabolites were also identified, while the pathways were mainly involved in D-glutamine and D-glutamate metabolism, and tyrosine metabolism, etc. Integrating transcriptomics and metabolomics analyses indicated that BBR directly regulated Carnitine C3:0, LPC (0:0/20:3), L-Glutamic Acid and FFA (15:0) by acting on SLC25A20, PNLIPRP1, PLA2G4C, GSR, GFPT2, GCLM, CTPS1, ACSL1, ACOT4 and ACOT2. 16S rRNA sequencing revealed that BBR could restore the balance of gut microbiota dysbiosis by significantly regulating the relative abundance of unclassified_Muribaculaceae and Lactobacillus_johnsonii. Conclusion This study demonstrated that BBR alleviates CAG through the regulation of the MAPK signaling pathway, metabolic disorders and gut microbiota dysbiosis, thereby revealing the complex mechanism of BBR in relation to alleviating CAG from multiple levels and perspectives.
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Affiliation(s)
- Lisheng Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xin Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jianyu Li
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Lijuan Zhang
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wenbin Wu
- Healthcare Office of the Service Bureau of Agency for Offices Administration of the Central Military Commission, Beijing, China
| | - Shizhang Wei
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenjun Zou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Sun X, Wu H, Tang L, Al-Danakh A, Jian Y, Gong L, Li C, Yu X, Zeng G, Chen Q, Yang D, Wang S. GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8 + T cells. Cancer Cell Int 2024; 24:308. [PMID: 39245709 PMCID: PMC11382498 DOI: 10.1186/s12935-024-03492-1] [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: 05/09/2024] [Accepted: 08/28/2024] [Indexed: 09/10/2024] Open
Abstract
Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8+ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.
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Affiliation(s)
- Xiaoxin Sun
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
- College of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Haotian Wu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ling Tang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Abdullah Al-Danakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yuli Jian
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Li Gong
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Congchen Li
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Xiao Yu
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Guang Zeng
- College of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Qiwei Chen
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
- Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University, 210096, Nanjing, China.
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
| | - Shujing Wang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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Wang T, Wang X, Zheng X, Guo Z, Mohsin A, Zhuang Y, Wang G. Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids. Biotechnol J 2024; 19:e2400163. [PMID: 39295558 DOI: 10.1002/biot.202400163] [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: 03/14/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 09/21/2024]
Abstract
The 3D multicellular tumor spheroid (MTS) model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the 2D monolayer model. In this study, we used multiomics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization, and mitochondrial function. An integrated analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, seven genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4, and SLC2A1, exhibited significant upregulation. Conversely, four genes, COA7, DLD, IFNGR1, and QRSL1, were significantly downregulated. Clinical prognostic analysis using the TCGA survival database indicated that high-expression groups of SLC2A1, ALDOC, and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.
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Affiliation(s)
- Tong Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
| | - Xueting Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
| | - Xuli Zheng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
| | - Zhongfang Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
| | - Yingping Zhuang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
- Qingdao Innovation Institute of East China University of Science and Technology, Shanghai, People's Republic of China
| | - Guan Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China
- Qingdao Innovation Institute of East China University of Science and Technology, Shanghai, People's Republic of China
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Gao XC, Zhou BH, Ji ZX, Li Q, Liu HN. Canopy FGF signaling regulator 3 affects prognosis, immune infiltration, and PI3K/AKT pathway in colon adenocarcinoma. World J Gastrointest Oncol 2024; 16:3284-3298. [PMID: 39072149 PMCID: PMC11271795 DOI: 10.4251/wjgo.v16.i7.3284] [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: 03/23/2024] [Revised: 05/14/2024] [Accepted: 06/04/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a malignant tumor of the digestive system. The mechanisms underlying COAD development and progression are still largely unknown. AIM To identify the role of canopy FGF signaling regulator 3 (CNPY3) in the development and progression of COAD by using bioinformatic tools and functional experiments. METHODS Bioinformatic data were downloaded from public databases. The associations of clinicopathological features, survival, and immune function with the expression of CNPY3 were analyzed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis were used to explore the related pathways. Then, quantitative real-time PCR and immunohistochemistry were used for validation of CNPY3 expression in clinical samples and tumor cell lines. Cell lines with CNPY3 knockdown were constructed to further analyze gene functions. The functional experiments included proliferation, invasion, migration and apoptosis assays. RESULTS In both the TCGA cohort and the merged dataset, elevated CNPY3 expression was observed in tumor tissues. High CNPY3 expression correlated with adverse survival and compromised immune functions. Functional enrichment analysis suggested that the pro-oncogenic properties of CNPY3 might be linked to the PI3K-AKT signaling pathway. CNPY3 expression was validated at both the RNA and protein levels. Functional assays indicated that cell proliferation, invasion, and migration were inhibited and cell apoptosis was promoted after CNPY3 knockdown. Additionally, Western blot results revealed the downregulation of key proteins in the PI3K/AKT pathway following CNPY3 knockdown. PI3K/AKT pathway activator reversed the decrease in proliferation, invasion, and migration and the increase in apoptosis. Notably, CNPY3 knockdown still affected the cells when the pathway was inhibited. CONCLUSION This study showed that CNPY3 is upregulated in COAD and might regulate COAD development and progression by the PI3K/AKT pathway. Thus, CNPY3 might be a promising therapeutic target.
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Affiliation(s)
- Xu-Can Gao
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Biao-Huan Zhou
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Zhou-Xin Ji
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Qiang Li
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
| | - Hui-Ning Liu
- Department of Anorectal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
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Zhang HR, Li TJ, Yu XJ, Liu C, Wu WD, Ye LY, Jin KZ. The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer. Cell Death Dis 2024; 15:244. [PMID: 38575607 PMCID: PMC10995196 DOI: 10.1038/s41419-024-06589-7] [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: 11/29/2023] [Revised: 02/28/2024] [Accepted: 03/04/2024] [Indexed: 04/06/2024]
Abstract
The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.
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Affiliation(s)
- Hui-Ru Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei-Ding Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Long-Yun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Kai-Zhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Zhang L, Deng Y, Yang J, Deng W, Li L. Neurotransmitter receptor-related gene signature as potential prognostic and therapeutic biomarkers in colorectal cancer. Front Cell Dev Biol 2023; 11:1202193. [PMID: 38099288 PMCID: PMC10720326 DOI: 10.3389/fcell.2023.1202193] [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: 04/07/2023] [Accepted: 11/21/2023] [Indexed: 12/17/2023] Open
Abstract
Background: Colorectal cancer is one of the most common malignant tumors worldwide. A various of neurotransmitter receptors have been found to be expressed in tumor cells, and the activation of these receptors may promote tumor growth and metastasis. This study aimed to construct a novel neurotransmitter receptor-related genes signature to predict the survival, immune microenvironment, and treatment response of colorectal cancer patients. Methods: RNA-seq and clinical data of colorectal cancer from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Neurotransmitter receptor-related gene were collected from publicly available data sources. The Weighted Gene Coexpression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) algorithms were employed to construct the Neurotransmitter receptor-related gene prognostic signature. Further analyses, functional enrichment, CIBERSORTx, The Tumor Immune Single Cell Center (TISCH), survival analysis, and CellMiner, were performed to analyze immune status and treatment responses. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were carried out to confirm the expression levels of prognostic genes. Results: By combining machine learning algorithm and WGCNA, we identified CHRNA3, GABRD, GRIK3, and GRIK5 as Neurotransmitter receptor-related prognostic genes signature. Functional enrichment analyses showed that these genes were enriched with cellular metabolic-related pathways, such as organic acid, inorganic acid, and lipid metabolism. CIBERSORTx and Single cell analysis showed that the high expression of genes were positively correlated with immunosuppressive cells infiltration, and the genes were mainly expressed in cancer-associated fibroblasts and endothelial cells. A nomogram was further built to predict overall survival (OS). The expression of CHRNA3, GABRD, GRIK3, and GRIK5 in cancer cells significantly impacted their response to chemotherapy. Conclusion: A neurotransmitter receptor-related prognostic gene signature was developed and validated in the current study, giving novel sights of neurotransmitter in predicting the prognostic and improving the treatment of CRC.
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Affiliation(s)
- Linjie Zhang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yizhang Deng
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jingbang Yang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Liren Li
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
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9
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Yang S, Li G, Yin X, Wang Y, Jiang X, Bian X, Fang T, Yin S, Zhang L, Xue Y. Cancer-associated fibroblast expression of glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer. J Pathol Clin Res 2023; 9:391-408. [PMID: 37395335 PMCID: PMC10397376 DOI: 10.1002/cjp2.333] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/12/2023] [Accepted: 05/12/2023] [Indexed: 07/04/2023]
Abstract
Glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a rate-limiting enzyme in hexosamine biosynthesis involved in the occurrence and progress of many cancers. What role it plays in gastric cancer (GC) is still unclear. In this study, transcriptome sequencing data from the Harbin Medical University (HMU)-GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined with the HMU-TCGA training cohort to analyze the biological function and clinical significance of GFPT2. The correlation of GFPT2 with immune cells and stromal cells was analyzed in the GC immune microenvironment through transcriptome sequencing data and a public single-cell sequencing database. In cell lines, GC tissues, and the tissue microarray, GFPT2 protein expression was confirmed by western blotting and immunohistochemistry. The mRNA of GFPT2 was highly expressed in the tumor (p < 0.001), and GC cells and tumors expressed high levels of GFPT2 protein. Compared to low expression, high GFPT2 mRNA expression was associated with higher levels of tumor invasion, higher pathological stages, and poor prognosis (p = 0.02) in GC patients. In a drug susceptibility analysis, GFPT2 mRNA expression was associated with multiple chemotherapeutic drug sensitivity, including docetaxel, paclitaxel, and cisplatin. Gene enrichment analysis found that GFPT2 was mainly primarily involved in the extracellular matrix receptor interaction pathway. The ESTIMATE, CIBERSORT, and ssGSEA algorithms showed that GFPT2 was associated with immune cell infiltration. In addition, GFPT2 was more likely to be expressed within cancer-associated fibroblasts (CAFs), and high levels of GFPT2 expression were highly correlated with four CAFs scores (all p < 0.05). Finally, a prognostic model to assess the risk of death in GC patients was constructed based on GFPT2 protein expression and lymph node metastasis rate. In conclusion, GFPT2 plays an essential role in the function of CAFs in GC. It can be used as a biomarker to assess GC prognosis and immune infiltration.
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Affiliation(s)
- Shuo Yang
- Department of Pathology, Basic Medical Science CollegeHarbin Medical UniversityHarbinPR China
| | - Guoli Li
- Department of Colorectal and Anal Surgery, Chifeng Municipal HospitalChifeng Clinical Medical School of Inner Mongolia Medical UniversityChifengPR China
| | - Xin Yin
- Department of Gastroenterological SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinPR China
| | - Yufei Wang
- Department of Gastroenterological SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinPR China
| | - Xinju Jiang
- Department of Pathology, Basic Medical Science CollegeHarbin Medical UniversityHarbinPR China
| | - Xiulan Bian
- Department of Pathology, Basic Medical Science CollegeHarbin Medical UniversityHarbinPR China
| | - Tianyi Fang
- Department of Gastroenterological SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinPR China
| | - Shengjie Yin
- Department of Medical Oncology, Municipal Hospital of ChifengInner Mongolia Autonomous RegionChifengPR China
| | - Lei Zhang
- Department of Pathology, Basic Medical Science CollegeHarbin Medical UniversityHarbinPR China
| | - Yingwei Xue
- Department of Gastroenterological SurgeryHarbin Medical University Cancer Hospital, Harbin Medical UniversityHarbinPR China
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10
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Guo Z, Li Z, Chen M, Qi X, Sun Z, Wu S, Hou X, Qiu M, Cao Y. Multi-omics analysis reveals the prognostic and tumor micro-environmental value of lumican in multiple cancer types. Front Mol Biosci 2023; 10:1158747. [PMID: 37692065 PMCID: PMC10484533 DOI: 10.3389/fmolb.2023.1158747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 08/14/2023] [Indexed: 09/12/2023] Open
Abstract
Background: Lumican (LUM), a proteoglycan of the extracellular matrix, has been reported to be involved in the regulation of immune escape processes, but the data supporting this phenomenon are not sufficient. In this study, we aimed to explore the links among LUM expression, survival, tumor microenvironment (TME), and immunotherapy in 33 cancer types. Methods: Data from several databases, such as UCSC Xena, GTEx, UALCAN, HPA, GEPIA2, TISIDB, PrognoScan, TIMER2, and GEO, as well as published studies, were used to determine the relationship between LUM expression and clinical features, TME, heterogeneity, and tumor stemness. Results: The expression of LUM was statistically different in most tumors versus normal tissues, both at the RNA and protein expression levels. High expression of LUM was typically associated with a poor prognosis in tumors. Additionally, immune scores, six immune cells, four immunosuppressive cells, cancer-associated fibroblasts (CAFs)-associated and immunosuppressive factors, tumor mutation burden (TMB), microsatellite instability (MSI), DNAss, and RNAss were all significantly associated with LUM. Among them, LUM expression displayed a significant positive correlation with CAFs and their factors, and exhibited immunosuppressive effects in six independent immunotherapy cohorts. Conclusion: Multi-omics analysis suggests that LUM may have been a prognostic marker, contributed to immunosuppression in the TME, and decreased the effectiveness of immune checkpoint inhibitors.
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Affiliation(s)
- Zehuai Guo
- Department of Internal Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Zeyun Li
- Guangzhou Huaxia Vocational College, Guangzhou, China
| | - Ming Chen
- Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xiangjun Qi
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xuenan Hou
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mengli Qiu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yang Cao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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11
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Yu D, Yang P, Lu X, Huang S, Liu L, Fan X. Single-cell RNA sequencing reveals enhanced antitumor immunity after combined application of PD-1 inhibitor and Shenmai injection in non-small cell lung cancer. Cell Commun Signal 2023; 21:169. [PMID: 37430270 DOI: 10.1186/s12964-023-01184-3] [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: 03/17/2023] [Accepted: 06/04/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have altered the clinical management of non-small cell lung cancer (NSCLC). However, the low response rate, severe immune-related adverse events (irAEs), and hyperprogressive disease following ICIs monotherapy require attention. Combination therapy may overcome these limitations and traditional Chinese medicine with immunomodulatory effects provides a promising approach. Shenmai injection (SMI) is a clinically effective adjuvant treatment for cancer with chemotherapy and radiotherapy. Therefore, the combined effects and mechanisms of SMI and programmed death-1 (PD-1) inhibitor against NSCLC was focused on this study. METHODS A Lewis lung carcinoma mouse model and a lung squamous cell carcinoma humanized mouse model were used to investigate the combined efficacy and safety of SMI and PD-1 inhibitor. The synergistic mechanisms of the combination therapy against NSCLC were explored using single-cell RNA sequencing. Validation experiments were performed using immunofluorescence analysis, in vitro experiment, and bulk transcriptomic datasets. RESULTS In both models, combination therapy alleviated tumor growth and prolonged survival without increasing irAEs. The GZMAhigh and XCL1high natural killer (NK) cell subclusters with cytotoxic and chemokine signatures increased in the combination therapy, while malignant cells from combination therapy were mainly in the apoptotic state, suggesting that mediating tumor cell apoptosis through NK cells is the main synergistic mechanisms of combination therapy. In vitro experiment confirmed that combination therapy increased secretion of Granzyme A by NK cells. Moreover, we discovered that PD-1 inhibitor and SMI combination blocked inhibitory receptors on NK and T cells and restores their antitumoral activity in NSCLC better than PD-1 inhibitor monotherapy, and immune and stromal cells exhibited a decrease of angiogenic features and attenuated cancer metabolism reprogramming in microenvironment of combination therapy. CONCLUSIONS This study demonstrated that SMI reprograms tumor immune microenvironment mainly by inducing NK cells infiltration and synergizes with PD-1 inhibitor against NSCLC, suggested that targeting NK cells may be an important strategy for combining with ICIs. Video Abstract.
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Affiliation(s)
- Dingyi Yu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Penghui Yang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaoyan Lu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
- Innovation Center in Zhejiang University, State Key Laboratory of Component-Based Chinese Medicine, Hangzhou, China.
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
- Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Shaoze Huang
- Zhejiang Engineering Research Center for Advanced Manufacturing of Traditional Chinese Medicine, Huzhou, China
| | - Li Liu
- Zhejiang Engineering Research Center for Advanced Manufacturing of Traditional Chinese Medicine, Huzhou, China.
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
- Innovation Center in Zhejiang University, State Key Laboratory of Component-Based Chinese Medicine, Hangzhou, China.
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
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12
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Zhao Z, Li T, Yuan Y, Zhu Y. What is new in cancer-associated fibroblast biomarkers? Cell Commun Signal 2023; 21:96. [PMID: 37143134 PMCID: PMC10158035 DOI: 10.1186/s12964-023-01125-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/05/2023] [Indexed: 05/06/2023] Open
Abstract
The tumor microenvironment is one of the important drivers of tumor development. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and actively participate in tumor development, invasion, metastasis, drug resistance, and other biological behaviors. CAFs are a highly heterogeneous group of cells, a reflection of the diversity of their origin, biomarkers, and functions. The diversity of CAF origin determines the complexity of CAF biomarkers, and CAF subpopulations expressing different biomarkers may play contrasting roles in tumor progression. In this review, we provide an overview of these emerging CAF biomarkers and the biological functions that they suggest, which may give a better understanding of the relationship between CAFs and tumor cells and be of great significance for breakthroughs in precision targeted therapy for tumors. Video Abstract.
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Affiliation(s)
- Zehua Zhao
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China
| | - Tianming Li
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, No. 155 of Nanjing Road, Heping District, Shenyang, 110001, China.
| | - Yanmei Zhu
- Department of Pathology, Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University), No. 44 of Xiaoheyan Road, Dadong District, Shenyang, 110042, China.
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13
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Paneque A, Fortus H, Zheng J, Werlen G, Jacinto E. The Hexosamine Biosynthesis Pathway: Regulation and Function. Genes (Basel) 2023; 14:genes14040933. [PMID: 37107691 PMCID: PMC10138107 DOI: 10.3390/genes14040933] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.
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Affiliation(s)
- Alysta Paneque
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Harvey Fortus
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Julia Zheng
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Guy Werlen
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Estela Jacinto
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
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14
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Prognostic Model and Immune Infiltration of Ferroptosis Subcluster-Related Modular Genes in Gastric Cancer. JOURNAL OF ONCOLOGY 2022; 2022:5813522. [PMID: 36276279 PMCID: PMC9584706 DOI: 10.1155/2022/5813522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/28/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric cancer (GC) is one of the gastrointestinal tumors with the highest mortality rate. The number of GC patients is still high. As a way of iron-dependent programmed cell death, ferroptosis activates lipid peroxidation and accumulates large reactive oxygen species. The role of ferroptosis in GC prognosis was underrepresented. The objective was to investigate the role of ferroptosis-related genes (FRGs) in the prognosis and development of GC. Methods Datasets of GC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database that include clinical information and RNA seq data. Through nonnegative matrix factorization (NMF) clustering, we identified and unsupervised cluster analysis of the expression matrix of FRGs. And we constructed the co-expression network between genes and clinical characteristics by consensus weighted gene co-expression network analysis (WGCNA). The prognostic model was constructed by univariate and multivariate regression analysis. The potential mechanisms of development and prognosis in GC were explored by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology (GO), tumor immune microenvironment (TIME), and tumor mutation burden (TMB). Results Two molecular subclusters with different expression patterns of FRGs were identified, which have significantly different survival states. Ferroptosis subcluster-related modular genes were identified by WGCNA. Based on 8 ferroptosis subcluster-related modular genes (collagen triple helix repeat containing 1 (CTHRC1), podoplanin (PDPN), procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), ATP-binding cassette subfamily A member 1 (ABCA1), G protein-coupled receptor 176 (GPR176), serpin family E member 1 (SERPINE1), dual specificity phosphatase 1 (DUSP1)) and clinicopathological features, a nomogram was constructed and validated for their predictive efficiency on GC prognosis. Through receiver operating characteristic (ROC) analysis, the results showed that the area under the curve (AUC) of 1-, 3-, and 5-year survival were 0.721, 0.747, and 0.803, respectively, indicating that the risk-scoring model we constructed had good prognosis efficacy in GC. The degree of immune infiltration in high-risk group was largely higher than low-risk group. It indicated that the immune cells have a good response in high-risk group of GC. The TMB of high-risk group was higher, which could generate more mutations and was more conducive to the body's resistance to the development of cancer. Conclusion The risk-scoring model based on 8 ferroptosis subcluster-related modular genes has shown outstanding advantages in predicting patient prognosis. The interaction of ferroptosis in GC development may provide new insights into exploring molecular mechanisms and targeted therapies for GC patients.
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