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Guo B, Gu J, Zhuang T, Zhang J, Fan C, Li Y, Zhao M, Chen R, Wang R, Kong Y, Xu S, Gao W, Liang L, Yu H, Han T. MicroRNA-126: From biology to therapeutics. Biomed Pharmacother 2025; 185:117953. [PMID: 40036996 DOI: 10.1016/j.biopha.2025.117953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/22/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025] Open
Abstract
MicroRNA-126 (miR-126) has emerged as one of the most extensively studied microRNAs in the context of human diseases, particularly in vascular disorders and cancer. Its high degree of conservation across vertebrates underscores its evolutionary significance and essential functional roles. Extensive research has been devoted to elucidating the molecular mechanisms through which miR-126 modulates key physiological and pathological processes, including angiogenesis, immune response, inflammation, tumor growth, and metastasis. Furthermore, miR-126 plays a causal role in the pathogenesis of various diseases, serving as potential biomarkers for disease prediction, diagnosis, prognosis and drug response, as well as a promising therapeutic target. In this review, we synthesize findings from 283 articles, focusing on the roles of miR-126 in critical biological processes such as cell development, survival, cycle regulation, proliferation, migration, invasion, communication, and metabolism. Additionally, miR-126 represents a promising candidate for miRNA-based therapeutic strategies. A comprehensive understanding and evaluation of miR-126 are crucial for advancing its clinical applications and therapeutic potential.
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Affiliation(s)
- Bei Guo
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Jia Gu
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tongtian Zhuang
- Department of Dermatology, Air Force Hospital of Northern Theater Command, Shenyang, China
| | - Jingbin Zhang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Chunyang Fan
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yiyao Li
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Mengdi Zhao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Ruoran Chen
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Rui Wang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yuan Kong
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Shuang Xu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Wei Gao
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Linlang Liang
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China
| | - Hao Yu
- Department of Metabolism and Endocrinology, General Hospital of Northern Theater Command, Shenyang, China.
| | - Tao Han
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.
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Schönberg J, Borlak J. miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures. Mol Cell Biochem 2025; 480:2573-2593. [PMID: 39424772 PMCID: PMC11961548 DOI: 10.1007/s11010-024-05129-3] [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: 06/21/2024] [Accepted: 09/29/2024] [Indexed: 10/21/2024]
Abstract
Primary non-function (PNF) of an allograft defines an irreversible graft failure and although rare, constitutes a life-threatening condition that requires high-urgency re-transplantation. Equally, drug induced acute liver failures (ALF) are seldom but the rapid loss of hepatic function may require orthotropic liver transplantation (OLT). Recently, we reported the development of a rodent PNF-disease model of fatty allografts and showed that a dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of PNF. Based on findings from the rat PNF-disease model, we selected 15 miRNA-biomarker candidates for clinical validation and performed RT-qPCRs in well-documented PNF cases following OLT of fatty allografts. To assess specificity and selectivity, we compared their regulation in pre- and intraoperative liver biopsies and pre- and post-operative blood samples of patients undergoing elective hepatobiliary surgery. Additionally, we assessed their regulation in drug induced ALF. We confirmed clinical relevance for 11 PNF-associated miRNAs and found expression of miRNA-27b-3p, miRNA-122-3p, miRNA-125a-5p, miRNA-125b-5p and miRNA-192-5p to correlate with the hepatic steatosis grades. Furthermore, we demonstrate selectivity and specificity for the biomarker candidates with opposite regulation of let-7b-5p, miRNA-122-5p, miRNA-125b-5p and miRNA-194-5p in blood samples of patients following successful OLTs and/or liver resection. Moreover, by considering findings from 21 independent ALF-studies, we observed nine PNF-associated miRNAs regulated in common. We report miRNAs highly regulated in PNF and ALF, and their common regulation in different diseases broadens the perspective as biomarker candidates. Our study warrants independent confirmation in randomized clinical trials.
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Affiliation(s)
- Juliette Schönberg
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
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Li CM, Sun T, Yang MJ, Yang Z, Li Q, Shi JL, Zhang C, Jin JF. Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice. World J Hepatol 2024; 16:1188-1198. [PMID: 39474574 PMCID: PMC11514617 DOI: 10.4254/wjh.v16.i10.1188] [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: 04/28/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen (APAP). However, the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.
AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.
METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury. C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment. We detected the effects of C2-FH on liver function, inflammatory response and complement activation. Additionally, RNA-sequencing (RNA-Seq) analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.
RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity, aspartate aminotransferase activity and lactate dehydrogenase, and reduced liver tissue necrosis caused by APAP. Moreover, it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury. RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.
CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.
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Affiliation(s)
- Chun-Mei Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Tian Sun
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Mou-Jie Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Zhi Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Qing Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jia-Lin Shi
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Chong Zhang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jun-Fei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
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Li CM, Sun T, Yang MJ, Yang Z, Li Q, Shi JL, Zhang C, Jin JF. Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice. World J Hepatol 2024; 16:1368-1378. [DOI: 10.4254/wjh.v16.i10.1368] [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: 04/28/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen (APAP). However, the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.
AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.
METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury. C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment. We detected the effects of C2-FH on liver function, inflammatory response and complement activation. Additionally, RNA-sequencing (RNA-Seq) analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.
RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity, aspartate aminotransferase activity and lactate dehydrogenase, and reduced liver tissue necrosis caused by APAP. Moreover, it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury. RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.
CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.
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Affiliation(s)
- Chun-Mei Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Tian Sun
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Mou-Jie Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Zhi Yang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Qing Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jia-Lin Shi
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Chong Zhang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Jun-Fei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- China-United States Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
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Li Z, Sun X. Epigenetic regulation in liver regeneration. Life Sci 2024; 353:122924. [PMID: 39038511 DOI: 10.1016/j.lfs.2024.122924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/24/2024]
Abstract
The liver is considered unique in its enormous capacity for regeneration and self-repair. In contrast to other regenerative organs (i.e., skin, skeletal muscle, and intestine), whether the adult liver contains a defined department of stem cells is still controversial. In order to compensate for the massive loss of hepatocytes following liver injury, the liver processes a precisely controlled transcriptional reprogram that can trigger cell proliferation and cell-fate switch. Epigenetic events are thought to regulate the organization of chromatin architecture and gene transcription during the liver regenerative process. In this review, we will summarize how changes to the chromatin by epigenetic modifiers are translated into cell fate transitions to restore liver homeostasis during liver regeneration.
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Affiliation(s)
- Zilong Li
- Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong, China.
| | - Xinyue Sun
- Department of Pharmacology, China Pharmaceutical University, 210009 Nanjing, Jiangsu, China
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Li P, Ma X, Huang D, Gu X. Exploring the roles of non-coding RNAs in liver regeneration. Noncoding RNA Res 2024; 9:945-953. [PMID: 38680418 PMCID: PMC11046251 DOI: 10.1016/j.ncrna.2024.04.003] [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: 02/14/2024] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Liver regeneration (LR) is a complex process encompassing three distinct phases: priming, proliferation phase and restoration, all influenced by various regulatory factors. After liver damage or partial resection, the liver tissue demonstrates remarkable restorative capacity, driven by cellular proliferation and repair mechanisms. The essential roles of non-coding RNAs (ncRNAs), predominantly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNA (circRNA), in regulating LR have been vastly studied. Additionally, the impact of ncRNAs on LR and their abnormal expression profiles during this process have been extensively documented. Mechanistic investigations have revealed that ncRNAs interact with genes involved in proliferation to regulate hepatocyte proliferation, apoptosis and differentiation, along with liver progenitor cell proliferation and migration. Given the significant role of ncRNAs in LR, an in-depth exploration of their involvement in the liver's self-repair capacity can reveal promising therapeutic strategies for LR and liver-related diseases. Moreover, understanding the unique regenerative potential of the adult liver and the mechanisms and regulatory factors of ncRNAs in LR are crucial for improving current treatment strategies and exploring new therapeutic approaches for various liver-related diseases. This review provides a brief overview of the LR process and the ncRNA expression profiles during this process. Furthermore, we also elaborate on the specific molecular mechanisms through which multiple key ncRNAs regulate the LR process. Finally, based on the expression characteristics of ncRNAs and their interactions with proliferation-associated genes, we explore their potential clinical application, such as developing predictive indicators reflecting liver regenerative activity and manipulating LR processes for therapeutic purposes.
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Affiliation(s)
- Penghui Li
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
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Shang T, Jiang T, Cui X, Pan Y, Feng X, Dong L, Wang H. Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases. Genes Dis 2024; 11:100996. [PMID: 38523677 PMCID: PMC10958229 DOI: 10.1016/j.gendis.2023.03.035] [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: 07/26/2022] [Revised: 02/13/2023] [Accepted: 03/19/2023] [Indexed: 03/26/2024] Open
Abstract
The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.
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Affiliation(s)
- Taiyu Shang
- School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
| | - Tianyi Jiang
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
| | - Xiaowen Cui
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
| | - Yufei Pan
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
| | - Xiaofan Feng
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
| | - Liwei Dong
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
| | - Hongyang Wang
- School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
- National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
- Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University & Ministry of Education, Shanghai 200438, China
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Qin D, Wang R, Ji J, Wang D, Lu Y, Cao S, Chen Y, Wang L, Chen X, Zhang L. Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function. Cell Biosci 2023; 13:159. [PMID: 37649095 PMCID: PMC10468867 DOI: 10.1186/s13578-023-01104-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND AND AIMS Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. RESULTS We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future.
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Affiliation(s)
- Dan Qin
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Rui Wang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Jinwei Ji
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Duo Wang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yuanyuan Lu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Shiyao Cao
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Yaqing Chen
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Liqiang Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
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Bellidifolin Inhibits SRY-Related High Mobility Group-Box Gene 9 to Block TGF-β Signalling Activation to Ameliorate Myocardial Fibrosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6841276. [PMID: 35586685 PMCID: PMC9110156 DOI: 10.1155/2022/6841276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/13/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022]
Abstract
Myocardial fibrosis is the main morphological change of ventricular remodelling caused by cardiovascular diseases, mainly manifested due to the excessive production of collagen proteins. SRY-related high mobility group-box gene 9 (SOX9) is a new target regulating myocardial fibrosis. Bellidifolin (BEL), the active component of G. acuta, can prevent heart damage. However, it is unclear whether BEL can regulate SOX9 to alleviate myocardial fibrosis. The mice were subjected to isoproterenol (ISO) to establish myocardial fibrosis, and human myocardial fibroblasts (HCFs) were activated by TGF-β1 in the present study. The pathological changes of cardiac tissue were observed by HE staining. Masson staining was applied to reveal the collagen deposition in the heart. The measurement for expression of fibrosis-related proteins, SOX9, and TGF-β1 signalling molecules adopted Western blot and immunohistochemistry. The effects of BEL on HCFs, activity were detected by CCK-8. The result showed that BEL did not affect cell viability. And, the data indicated that BEL inhibited the elevations in α-SMA, Collagen I, and Collagen III by decreasing SOX9 expression. Additionally, SOX9 suppression by siRNA downregulated the TGF-β1 expression and prevented Smad3 phosphorylation, as supported by reducing the expression of α-SMA, Collagen I, and Collagen III. In vivo study verified that BEL ameliorated myocardial fibrosis by inhibiting SOX9. Therefore, BEL inhibited SOX9 to block TGF-β1 signalling activation to ameliorate myocardial fibrosis.
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Zou Q, Liu C, Hu N, Wang W, Wang H. miR-126 ameliorates multiple organ dysfunction in septic rats by regulating the differentiation of Th17/Treg. Mol Biol Rep 2022; 49:2985-2998. [PMID: 35122598 PMCID: PMC8817156 DOI: 10.1007/s11033-022-07121-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 01/04/2022] [Indexed: 10/25/2022]
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Liu S, Qin D, Yan Y, Wu J, Meng L, Huang W, Wang L, Chen X, Zhang L. Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9 + hepatocyte fate. iScience 2021; 24:103003. [PMID: 34505013 PMCID: PMC8417399 DOI: 10.1016/j.isci.2021.103003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/13/2021] [Accepted: 08/16/2021] [Indexed: 11/26/2022] Open
Abstract
Recent research has indicated the adult liver Sox9+ cells located in the portal triads contribute to the physiological maintenance of liver mass and injury repair. However, the physiology and pathology regulation mechanisms of adult liver Sox9+ cells remain unknown. Here, PPARα and FXR bound to the shared site in Sox9 promoter with opposite transcriptional outputs. PPARα activation enhanced the fatty acid β-oxidation, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production, thus promoting proliferation and differentiation of Sox9+ hepatocytes along periportal (PP)-perivenous (PV) axis. However, FXR activation increased glycolysis but decreased OXPHOS and ATP production, therefore preventing proliferation of Sox9+ hepatocytes along PP-PV axis by promoting Sox9+ hepatocyte self-renewal. Our research indicates that metabolic nuclear receptors play critical roles in liver progenitor Sox9+ hepatocyte homeostasis to initiate or terminate liver injury-induced cell proliferation and differentiation, suggesting that PPARα and FXR are potential therapeutic targets for modulating liver regeneration.
PPARα promotes Sox9 expression and FXR inhibits Sox9 expression PPARα promotes proliferation and differentiation of Sox9+ hepatocytes FXR promotes Sox9+ hepatocyte self-renewal PPARα and FXR coordinate energy metabolism to regulate Sox9+ hepatocyte fate
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Affiliation(s)
- Shenghui Liu
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
| | - Dan Qin
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
| | - Yi Yan
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
| | - Jiayan Wu
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
| | - Lihua Meng
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Liqiang Wang
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing 100853, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing 100853, China
| | - Lisheng Zhang
- College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China
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Chen M, Lu C, Lu H, Zhang J, Qin D, Liu S, Li X, Zhang L. Farnesoid X receptor via Notch1 directs asymmetric cell division of Sox9 + cells to prevent the development of liver cancer in a mouse model. Stem Cell Res Ther 2021; 12:232. [PMID: 33845903 PMCID: PMC8042944 DOI: 10.1186/s13287-021-02298-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. The rate of symmetric division increases as more cancer stem cells (CSCs) become malignant; however, the signaling pathway network involved in CSC division remains elusive. FXR (Farnesoid X receptor), a ligand-activated transcription factor, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating the role of FXR in the regulation of the cell division of CSCs. Methods The FXR target gene and downstream molecular mechanisms were confirmed by qRT-PCR, Western blot, luciferase reporter assay, EMAS, Chip, and IF analyses. Pulse-chase BrdU labeling and paired-cell experiments were used to detect the cell division of liver CSCs. Gain- and loss-of-function experiments in Huh7 cells and mouse models were performed to support findings and elucidate the function and underlying mechanisms of FXR-Notch1 in liver CSC division. Results We demonstrated that activation of Notch1 was significantly elevated in the livers of hepatocellular carcinoma (HCC) in Farnesoid X receptor-knockout (FXR-KO) mice and that FXR expression negatively correlated with Notch1 level during chronic liver injury. Activation of FXR induced the asymmetric divisions of Sox9+ liver CSCs and ameliorated liver injury. Mechanistically, FXR directs Sox9+ liver CSCs from symmetry to asymmetry via inhibition of Notch1 expression and activity. Deletion of FXR signaling or over-expression of Notch1 greatly increased Notch1 expression and activity along with ACD reduction. FXR inhibited Notch1 expression by directly binding to its promoter FXRE. FXR also positively regulated Numb expression, contributing to a feedback circuit, which decreased Notch1 activity and directed ACD. Conclusion Our findings suggest that FXR represses Notch1 expression and directs ACD of Sox9+ cells to prevent the development of liver cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02298-6.
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Affiliation(s)
- Mi Chen
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Chenxia Lu
- The Clinical Medical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Hanwen Lu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Junyi Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Dan Qin
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Shenghui Liu
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiaodong Li
- Hubei Provincial Hospital of TCM, Hubei Provincial Academy of TCM, Wuhan, 430061, China
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China.
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