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1
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Nagaraj M, Emmagouni SKG, Chaurasiya V, Li L, Nguyen VD, Keskitalo S, Varjosalo M, Zhou Y, Haridas PAN, Olkkonen VM. Insight into the function of the Golgi membrane protein GOLM1 in cholangiocytes through interactomic analysis. FEBS Lett 2025; 599:1299-1316. [PMID: 39891560 DOI: 10.1002/1873-3468.70001] [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: 09/14/2024] [Revised: 12/10/2024] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
GOLM1, a Golgi membrane protein, is upregulated in cancers and liver diseases. Analysis of public RNAseq data from healthy human liver suggested that GOLM1 is predominantly expressed in cholangiocytes. Therefore, this study was initiated to understand the molecular functions of GOLM1 in cholangiocytes through protein interactomics. The findings reveal a number of putative GOLM1-interacting partners involved in cellular regimes such as mitochondrial and Golgi functions, ribonucleoprotein biogenesis, cell cycle, and basement membrane organization. Further, to validate select key roles, GOLM1 was silenced in MMNK-1 cholangiocytes and the effects on cell functions were studied. The silencing resulted in impaired mitochondrial function, reduced mitochondrial and P-body markers, increased apoptosis, and reduced cell adhesion, suggesting crucial roles of GOLM1 in maintaining normal cholangiocyte metabolism and function.
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Affiliation(s)
- Meghana Nagaraj
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland
- Doctoral Programme in Integrative Life Science, University of Helsinki, Finland
| | | | - Vaishali Chaurasiya
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland
| | - Luyang Li
- Systems Immunity University Research Institute, and Division of Infection and Immunity, Cardiff University, UK
| | - Van Dien Nguyen
- Systems Immunity University Research Institute, and Division of Infection and Immunity, Cardiff University, UK
| | - Salla Keskitalo
- Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Finland
- HiLIFE-Proteomics Unit, Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Markku Varjosalo
- Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Finland
- HiLIFE-Proteomics Unit, Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Finland
| | - You Zhou
- Systems Immunity University Research Institute, and Division of Infection and Immunity, Cardiff University, UK
| | - P A Nidhina Haridas
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland
- Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland
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2
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Xu R, Hao Y, Liu Y, Ji B, Tian W, Zhang W. Functional mechanisms and potential therapeutic strategies for lactylation in liver diseases. Life Sci 2025; 363:123395. [PMID: 39809380 DOI: 10.1016/j.lfs.2025.123395] [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: 11/07/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Lactylation, a novel form of lactate-mediated protein post-translational modification (PTM), has been identified as a crucial regulator of gene expression and protein function through the modification of both histone and non-histone proteins. Liver disease is frequently characterized by a reprogramming of glucose metabolism and subsequent lactate accumulation. Recent research has implicated lactylation in a diverse array of hepatic pathologies, including liver injury, non-alcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Consequently, lactylation has emerged as a pivotal regulatory mechanism in liver disease pathogenesis. This review aims to elucidate the intricate regulatory and functional mechanisms underlying lactylation, synthesize recent advancements in its role in various liver diseases, and highlight its potential as a therapeutic target for future interventions in hepatic disorders.
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Affiliation(s)
- Rong Xu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yitong Hao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yahui Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Weibo Tian
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
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3
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Ye J, Gao X, Huang X, Huang S, Zeng D, Luo W, Zeng C, Lu C, Lu L, Huang H, Mo K, Huang J, Li S, Tang M, Wu T, Mai R, Luo M, Xie M, Wang S, Li Y, Lin Y, Liang R. Integrating Single-Cell and Spatial Transcriptomics to Uncover and Elucidate GP73-Mediated Pro-Angiogenic Regulatory Networks in Hepatocellular Carcinoma. RESEARCH (WASHINGTON, D.C.) 2024; 7:0387. [PMID: 38939041 PMCID: PMC11208919 DOI: 10.34133/research.0387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/21/2024] [Indexed: 06/29/2024]
Abstract
Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.
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Affiliation(s)
- Jiazhou Ye
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Nanning 530021, China
| | - Xing Gao
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Xi Huang
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Shilin Huang
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Dandan Zeng
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Wenfeng Luo
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Can Zeng
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Lu Lu
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Hongyang Huang
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Kaixiang Mo
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Julu Huang
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Shizhou Li
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Minchao Tang
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Tianzhun Wu
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Rongyun Mai
- Department of Hepatobiliary Surgery,
Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
| | - Min Luo
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Mingzhi Xie
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Shan Wang
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Nanning 530021, China
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Yongqiang Li
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Yan Lin
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Rong Liang
- Guangxi Liver Cancer Diagnosis and Treatment Project Technology Research Center, Nanning 530021, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Nanning 530021, China
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
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Yao M, Fang RF, Xie Q, Xu M, Sai WL, Yao DF. Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2350-2361. [PMID: 38994143 PMCID: PMC11236219 DOI: 10.4251/wjgo.v16.i6.2350] [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: 02/22/2024] [Revised: 04/02/2024] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Rong-Fei Fang
- Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qun Xie
- Department of Infectious Diseases, Haian People’s Hospital, Haian 226600, Jiangsu Province, China
| | - Min Xu
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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5
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Yao M, Fang RF, Xie Q, Xu M, Sai WL, Yao DF. Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2814-2825. [DOI: 10.4251/wjgo.v16.i6.2814] [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: 02/22/2024] [Revised: 04/02/2024] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.
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Affiliation(s)
- Min Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Rong-Fei Fang
- Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qun Xie
- Department of Infectious Diseases, Haian People’s Hospital, Haian 226600, Jiangsu Province, China
| | - Min Xu
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Li Sai
- Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Department of Immunology, Medical School of Nantong University and Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Zhang L, Li S, Zhang D, Yin C, Wang Z, Chen R, Cheng N, Bai Y. Value of GPR, APPRI and FIB-4 in the early diagnosis of hepatocellular carcinoma: a prospective cohort study. Jpn J Clin Oncol 2024; 54:129-136. [PMID: 37869774 DOI: 10.1093/jjco/hyad147] [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: 08/15/2023] [Accepted: 10/05/2023] [Indexed: 10/24/2023] Open
Abstract
OBJECTIVE There is an urgent need for novel biomarkers that are inexpensive, effective and easily accessible to complement the early diagnosis of hepatocellular carcinoma. This study aimed to analyze the relationship between serum gamma-glutamate-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index, fibrosis index based on four factors and the risk of hepatocellular carcinoma, and to determine the optimal cut-offs for predicting hepatocellular carcinoma. METHODS Based on a prospective cohort study, 44 215 participants who were cancer-free at baseline (2011-13) were included in the study. Cox proportional hazard models and receiver operating characteristics curves were used to analyze the diagnostic value and optimal cut-off value of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors in predicting hepatocellular carcinoma patients. RESULTS Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors can be used as early independent predictors of hepatocellular carcinoma risk. The risk of hepatocellular carcinoma in the fourth quantile of gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index was 4.04 times (hazard ratio = 4.04, 95% confidence interval: 2.09, 7.80) and 2.59 times (hazard ratio = 2.59, 95% confidence interval: 1.45, 4.61), respectively, compared with the first quantile. With fibrosis index based on four factors first quantile as a reference, fibrosis index based on four factors fourth quantile had the highest risk (hazard ratio = 18.58, 95% confidence interval: 7.55, 45.72). Receiver operating characteristic results showed that fibrosis index based on four factors had a stronger ability to predict the risk of hepatocellular carcinoma (area under curve = 0.81, 95% confidence interval: 0.80, 0.81), and similar results were shown for gender stratification. In the total population, the optimal cut-off values of gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were 0.208, 0.629 and 1.942, respectively. CONCLUSIONS Gamma-glutamyl-transpeptidase to platelet ratio, alkaline phosphatase-to-platelet ratio index and fibrosis index based on four factors were independent predictors of hepatocellular carcinoma risk. Amongst them, fibrosis index based on four factors shows a stronger predictive ability for hepatocellular carcinoma risk, and gamma-glutamyl-transpeptidase to platelet ratio and alkaline phosphatase-to-platelet ratio index can be used as complementary indicators.
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Affiliation(s)
- Lizhen Zhang
- Department of Epidemiology and Statistics, School of Public Health, Lanzhou University, Lanzhou, China
| | - Siyu Li
- Department of Epidemiology, Baotou Medical College, Baotou, China
| | - Desheng Zhang
- Jinchuan Group Co., LTD, Jinchuan Company Staff Hospital, Jinchang, China
| | - Chun Yin
- Jinchuan Group Co., LTD, Jinchuan Company Staff Hospital, Jinchang, China
| | - Zhongge Wang
- Department of Epidemiology and Statistics, School of Public Health, Lanzhou University, Lanzhou, China
| | - Ruirui Chen
- Department of Epidemiology and Statistics, School of Public Health, Lanzhou University, Lanzhou, China
| | - Ning Cheng
- College of Basic Medicine, Lanzhou University, Lanzhou, China
| | - Yana Bai
- Department of Epidemiology and Statistics, School of Public Health, Lanzhou University, Lanzhou, China
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7
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Shahini E, Pasculli G, Solimando AG, Tiribelli C, Cozzolongo R, Giannelli G. Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int J Mol Sci 2023; 24:4286. [PMID: 36901717 PMCID: PMC10001986 DOI: 10.3390/ijms24054286] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Giuseppe Pasculli
- National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), University of Bari “A. Moro”, 70121 Bari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Director, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
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GOLM1 depletion modifies cellular sphingolipid metabolism and adversely affects cell growth. J Lipid Res 2022; 63:100259. [PMID: 35948172 PMCID: PMC9475319 DOI: 10.1016/j.jlr.2022.100259] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022] Open
Abstract
Golgi membrane protein 1 (GOLM1) is a Golgi-resident type 2 transmembrane protein known to be overexpressed in several cancers, including hepatocellular carcinoma (HCC), as well as in viral infections. However, the role of GOLM1 in lipid metabolism remains enigmatic. In this study, we employed siRNA-mediated GOLM1 depletion in Huh-7 HCC cells to study the role of GOLM1 in lipid metabolism. Mass spectrometric lipidomic analysis in GOLM1 knockdown cells showed an aberrant accumulation of sphingolipids, such as ceramides, hexosylceramides, dihexosylceramides, sphinganine, sphingosine, and ceramide phosphate, along with cholesteryl esters. Furthermore, we observed a reduction in phosphatidylethanolamines and lysophosphatidylethanolamines. In addition, Seahorse extracellular flux analysis indicated a reduction in mitochondrial oxygen consumption rate upon GOLM1 depletion. Finally, alterations in Golgi structure and distribution were observed both by electron microscopy imaging and immunofluorescence microscopy analysis. Importantly, we found that GOLM1 depletion also affected cell proliferation and cell cycle progression in Huh-7 HCC cells. The Golgi structural defects induced by GOLM1 reduction might potentially affect the trafficking of proteins and lipids leading to distorted intracellular lipid homeostasis, which may result in organelle dysfunction and altered cell growth. In conclusion, we demonstrate that GOLM1 depletion affects sphingolipid metabolism, mitochondrial function, Golgi structure, and proliferation of HCC cells.
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9
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Baj J, Bryliński Ł, Woliński F, Granat M, Kostelecka K, Duda P, Flieger J, Teresiński G, Buszewicz G, Furtak-Niczyporuk M, Portincasa P. Biomarkers and Genetic Markers of Hepatocellular Carcinoma and Cholangiocarcinoma-What Do We Already Know. Cancers (Basel) 2022; 14:1493. [PMID: 35326644 PMCID: PMC8946081 DOI: 10.3390/cancers14061493] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with an increasing worldwide mortality rate. Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In both types of cancers, early detection is very important. Biomarkers are a relevant part of diagnosis, enabling non-invasive detection and control of cancer recurrence, as well as in the application of screening tests in high-risk groups. Furthermore, some of these biomarkers are useful in controlling therapy and treatment selection. Detection of some markers presents higher sensitivity and specificity in combination with other markers when compared with a single detection. Some gene aberrations are also prognostic markers in the two types of cancers. In the following review, we discuss the most common biomarkers and genetic markers currently being used in the diagnosis of hepatocellular carcinoma and cholangiocarcinoma.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Łukasz Bryliński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Filip Woliński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Michał Granat
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Katarzyna Kostelecka
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Piotr Duda
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (M.G.); (K.K.); (P.D.)
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Grzegorz Teresiński
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (Ł.B.); (F.W.); (G.T.); (G.B.)
| | | | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
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Pan B, Yang M, Wei X, Li W, Wang K, Yang M, Lu D, Wang R, Cen B, Xu X. Interleukin-2 inducible T-cell kinase: a potential prognostic biomarker and tumor microenvironment remodeling indicator for hepatocellular carcinoma. Aging (Albany NY) 2021; 13:18620-18644. [PMID: 34282055 PMCID: PMC8351695 DOI: 10.18632/aging.203306] [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: 11/24/2020] [Accepted: 06/23/2021] [Indexed: 11/25/2022]
Abstract
Background: The heterogeneous tumor microenvironment (TME) contributes to poor prognosis of hepatocellular carcinoma (HCC). However, determining the modulation of TME during HCC progression remains a challenge. Methods: Herein, the stromal score and immune score of HCC samples from The Cancer Genome Atlas database were calculated using the ESTIMATE algorithm and differentially expressed genes (DEGs) were obtained. Key DEGs were identified based on a protein-protein interaction network and survival analysis. Immunohistochemistry was carried out using primary samples to evaluate key DEGs expression. The CIBERSORT algorithm was applied to evaluate immune components. Gene Set Enrichment Analysis (GSEA) and correlation analysis were carried out to determine the relationship between key DEGs and tumor-infiltrating immune cells (TICs). Results: The stromal score, immune score and estimate score correlated significantly with 1-year recurrence-free survival of patients with HCC. Interleukin-2 inducible T-cell kinase (ITK) was identified as the most prognostic DEG for patients with HCC. GSEA revealed that genes in the high ITK subgroup were enriched in inflammatory-immunological terms. CIBERSORT analysis identified nine TIC subsets that correlated with ITK expression. Conclusion: We identified ITK as a novel indicator for early post-surgery tumor recurrence and microenvironment remodeling in HCC, providing a potential therapeutic target to treat HCC.
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Affiliation(s)
- Binhua Pan
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Wangyao Li
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Kun Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Mengfan Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Rui Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Beini Cen
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a low survival rate. The identification of mechanisms underlying the development of HCC helps uncover cellular and molecular targets for the diagnosis, prevention, and treatment of HCC. Golgi protein 73 (GP73) level is upregulated in HCC patients and potentially can be a therapeutic target. Despite many studies devoted to GP73 as a marker for HCC early diagnosis, there is little discussion about the function of GP73 in HCC tumorigenesis. Given the poor response to currently available HCC therapies, a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC. The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis. Its roles in other types of cancer are also discussed.
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Affiliation(s)
- Yanan Wang
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA, USA
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA, USA
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12
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common liver malignancies and is a leading cause of cancer-related deaths. Most HCC patients are diagnosed at an advanced stage and current treatments show poor therapeutic efficacy. It is particularly urgent to explore early diagnosis methods and effective treatments of HCC. There are a growing number of studies that show GOLM1 is one of the most promising markers for early diagnosis and prognosis of HCC. It is also involved in immune regulation, activation and degradation of intracellular signaling factors and promotion of epithelial-mesenchymal transition. GOLM1 can promote HCC progression and metastasis. The understanding of the GOLM1 regulation mechanism may provide new ideas for the diagnosis, monitoring and treatment of HCC.
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Affiliation(s)
- Jiuliang Yan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Binghai Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Hui Li
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Lei Guo
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Qinghai Ye
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
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