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Rattanasinchai C, Navasumrit P, Chornkrathok C, Ruchirawat M. Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167521. [PMID: 39369614 DOI: 10.1016/j.bbadis.2024.167521] [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: 05/27/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive. METHODS The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated. RESULTS Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations. CONCLUSIONS IGF-1R plays a critical role in maintaining iCCA-stem like cell populations. GENERAL SIGNIFICANCE Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.
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Affiliation(s)
- Chotirat Rattanasinchai
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Panida Navasumrit
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Chidchanok Chornkrathok
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Mathuros Ruchirawat
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand.
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Yang L, Xia H, Smith K, Gilbertsen AJ, Jbeli AH, Abrahante JE, Bitterman PB, Henke CA. Tumor suppressors RBL1 and PTEN are epigenetically silenced in IPF mesenchymal progenitor cells by a CD44/Brg1/PRMT5 regulatory complex. Am J Physiol Lung Cell Mol Physiol 2024; 327:L949-L963. [PMID: 39406384 PMCID: PMC11684952 DOI: 10.1152/ajplung.00182.2024] [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: 06/13/2024] [Revised: 09/20/2024] [Accepted: 10/14/2024] [Indexed: 12/06/2024] Open
Abstract
The idiopathic pulmonary fibrosis (IPF) lung contains mesenchymal progenitor cells (MPCs) that display durable activation of oncogenic signaling and cell-autonomous fibrogenicity in vivo. Prior work identified a CD44/Brg1/PRMT5 nuclear regulatory module in IPF MPCs that increased the expression of genes positively regulating pluripotency and self-renewal. Left unanswered is how IPF MPCs evade negative regulation of self-renewal. Here we sought to identify mechanisms disabling negative regulation of self-renewal in IPF MPCs. We demonstrate that expression of the tumor suppressor genes rbl1 and pten is decreased in IPF MPCs. The mechanism involves the CD44-facilitated association of the chromatin remodeler Brg1 with the histone-modifying methyltransferase PRMT5. Brg1 enhances chromatin accessibility leading to PRMT5-mediated methylation of H3R8 and H4R3 on the rbl1 and pten genes, repressing their expression. Genetic knockdown or pharmacological inhibition of either Brg1 or PRMT5 restored RBL1 and PTEN expression reduced IPF MPC self-renewal in vitro and inhibited IPF MPC-mediated pulmonary fibrosis in vivo. Our studies indicate that the CD44/Brg1/PRMT5 regulatory module not only functions to activate positive regulators of pluripotency and self-renewal but also functions to repress tumor suppressor genes rbl1 and pten. This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF.NEW & NOTEWORTHY Here we demonstrate that a CD44/Brg1/PRMT5 epigenetic regulatory module represses the tumor suppressor genes RBL1 and PTEN in IPF mesenchymal progenitor cells, thereby promoting their self-renewal and maintenance of a critical pool of fibrogenic mesenchymal progenitor cells.
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Affiliation(s)
- Libang Yang
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Hong Xia
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Karen Smith
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Adam J Gilbertsen
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Aiham H Jbeli
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Juan E Abrahante
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota, United States
| | - Peter B Bitterman
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
| | - Craig A Henke
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States
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3
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Zhang Y, Ren L, Tian Y, Guo X, Wei F, Zhang Y. Signaling pathways that activate hepatic stellate cells during liver fibrosis. Front Med (Lausanne) 2024; 11:1454980. [PMID: 39359922 PMCID: PMC11445071 DOI: 10.3389/fmed.2024.1454980] [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: 06/26/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Liver fibrosis is a complex process driven by various factors and is a key feature of chronic liver diseases. Its essence is liver tissue remodeling caused by excessive accumulation of collagen and other extracellular matrix. Activation of hepatic stellate cells (HSCs), which are responsible for collagen production, plays a crucial role in promoting the progression of liver fibrosis. Abnormal expression of signaling pathways, such as the TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these pathways, providing valuable insights into the development of liver fibrosis. Here, we will review six signaling pathways such as TGF-β/Smads that have been studied more in recent years.
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Affiliation(s)
- Youtian Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Long Ren
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yinting Tian
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Guo
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yawu Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
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4
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Tan Y, Zhou Y, Zhang W, Wu Z, Xu Q, Wu Q, Yang J, Lv T, Yan L, Luo H, Shi Y, Yang J. Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis. Cell Oncol (Dordr) 2024; 47:1167-1181. [PMID: 38326640 DOI: 10.1007/s13402-024-00919-9] [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] [Accepted: 01/11/2024] [Indexed: 02/09/2024] Open
Abstract
PURPOSE The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy. METHODS Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl4). RESULTS Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment. CONCLUSION Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.
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Affiliation(s)
- Yifei Tan
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
- Department of Ultrasonography, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yongjie Zhou
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Zhang
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhenru Wu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Qing Xu
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Qiong Wu
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
| | - Jian Yang
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
| | - Tao Lv
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
| | - Lvnan Yan
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China
| | - Hong Luo
- Department of Ultrasonography, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Yujun Shi
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China.
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China.
| | - Jiayin Yang
- Department of Liver Transplantation Center and Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China.
- Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu, 610041, China.
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Liu H, Yue L, Hong W, Zhou J. SMARCA4 (BRG1) activates ABCC3 transcription to promote hepatocellular carcinogenesis. Life Sci 2024; 347:122605. [PMID: 38642845 DOI: 10.1016/j.lfs.2024.122605] [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: 12/28/2023] [Revised: 03/08/2024] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a lead cause of cancer-related deaths. In the present study we investigated the role of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in HCC the pathogenesis focusing on identifying novel transcription targets. METHODS AND MATERIALS Hepatocellular carcinogenesis was modeled in mice by diethylnitrosamine (DEN). Cellular transcriptome was evaluated by RNA-seq. RESULTS Hepatocellular carcinoma was appreciably retarded in BRG1 knockout mice compared to wild type littermates. Transcriptomic analysis identified ATP Binding Cassette Subfamily C Member 3 (ABCC3) as a novel target of BRG1. BRG1 over-expression in BRG1low HCC cells (HEP1) up-regulated whereas BRG1 depletion in BRG1high HCC cells (SNU387) down-regulated ABCC3 expression. Importantly, BRG1 was detected to directly bind to the ABCC3 promoter to activate ABCC3 transcription. BRG1 over-expression in HEP1 cells promoted proliferation and migration, both of which were abrogated by ABCC3 silencing. On the contrary, BRG1 depletion in SNU387 cells decelerated proliferation and migration, both of which were rescued by ABCC3 over-expression. Importantly, high BRG1/ABCC3 expression predicted poor prognosis in HCC patients. Mechanistically, ABCC3 regulated hepatocellular carcinogenesis possibly by influencing lysosomal homeostasis. SIGNIFICANCE In conclusion, our data suggest that targeting BRG1 and its downstream target ABCC3 can be considered as a reasonable approach for the intervention of hepatocellular carcinoma.
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Affiliation(s)
- Huimin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Linbo Yue
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Wenxuan Hong
- Institute of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Junjing Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
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Wu X, Meng Y, Chen J, Zhang Y, Xu H. Ablation of Brg1 in fibroblast/myofibroblast lineages attenuates renal fibrosis in mice with diabetic nephropathy. Life Sci 2024; 344:122578. [PMID: 38537899 DOI: 10.1016/j.lfs.2024.122578] [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: 01/31/2024] [Revised: 03/03/2024] [Accepted: 03/18/2024] [Indexed: 04/05/2024]
Abstract
AIMS Diabetic nephropathy (DN) is one of the most common complications of diabetes and represents a prototypical form of chronic kidney disease (CKD). Interstitial fibrosis is a key pathological feature of DN. During DN-associated renal fibrosis, resident fibroblasts trans-differentiate into myofibroblasts to remodel the extracellular matrix, the underlying epigenetic mechanism of which is not entirely clear. METHODS Diabetic nephropathy was induced in C57B6/j mice by a single injection with streptozotocin (STZ). Gene expression was examined by quantitative PCR and Western blotting. Renal fibrosis was evaluated by PicroSirius Red staining. RESULTS We report that expression of Brg1, a chromatin remodeling protein, in renal fibroblasts was up-regulated during DN pathogenesis as assessed by single-cell RNA-seq. Treatment with high glucose similarly augmented Brg1 expression in primary renal fibroblasts in vitro. Importantly, Brg1 ablation in quiescent renal fibroblasts or in mature myofibroblasts equivalently attenuated renal fibrosis in the context of diabetic nephropathy in mice. Additionally, administration with a small-molecule Brg1 inhibitor PFI-3 ameliorated renal fibrosis and improved renal function in mice induced to develop DN. SIGNIFICANCE In conclusion, our data provide novel genetic evidence that links Brg1 to fibroblast-myofibroblast transition and renewed rationale for targeting Brg1 in the intervention of DN-associated renal fibrosis.
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Affiliation(s)
- Xiaoyan Wu
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Yufei Meng
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Jinsi Chen
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Yongchen Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Huihui Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China.
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7
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Sun YM, Wu Y, Li GX, Liang HF, Yong TY, Li Z, Zhang B, Chen XP, Jin GN, Ding ZY. TGF-β downstream of Smad3 and MAPK signaling antagonistically regulate the viability and partial epithelial-mesenchymal transition of liver progenitor cells. Aging (Albany NY) 2024; 16:6588-6612. [PMID: 38604156 PMCID: PMC11042936 DOI: 10.18632/aging.205725] [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: 05/12/2023] [Accepted: 03/18/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances. RESULTS By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT. CONCLUSION These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.
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Affiliation(s)
- Yi-Min Sun
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Present address: Department of Gastrointestinal Surgery, Affiliated First Hospital, Yangtze University, Jingzhou, Hubei 434000, China
| | - Yu Wu
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Gan-Xun Li
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Hui-Fang Liang
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Tu-Ying Yong
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Guan-Nan Jin
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Present address: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ze-Yang Ding
- Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
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Papoutsoglou P, Pineau R, Leroux R, Louis C, L'Haridon A, Foretek D, Morillon A, Banales JM, Gilot D, Aubry M, Coulouarn C. TGFβ-induced long non-coding RNA LINC00313 activates Wnt signaling and promotes cholangiocarcinoma. EMBO Rep 2024; 25:1022-1054. [PMID: 38332153 PMCID: PMC10933437 DOI: 10.1038/s44319-024-00075-z] [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: 09/26/2022] [Revised: 01/13/2024] [Accepted: 01/18/2024] [Indexed: 02/10/2024] Open
Abstract
Cholangiocarcinoma is a devastating liver cancer characterized by high aggressiveness and therapy resistance, resulting in poor prognosis. Long non-coding RNAs and signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ), frequently contribute to cholangiocarcinogenesis. Here, we explore novel effectors of TGFβ signalling in cholangiocarcinoma. LINC00313 is identified as a novel TGFβ target gene. Gene expression and genome-wide chromatin accessibility profiling reveal that nuclear LINC00313 transcriptionally regulates genes involved in Wnt signalling, such as the transcriptional activator TCF7. LINC00313 gain-of-function enhances TCF/LEF-dependent transcription, promotes colony formation in vitro and accelerates tumour growth in vivo. Genes affected by LINC00313 over-expression in CCA tumours are associated with KRAS and TP53 mutations and reduce overall patient survival. Mechanistically, ACTL6A and BRG1, subunits of the SWI/SNF chromatin remodelling complex, interact with LINC00313 and affect TCF7 and SULF2 transcription. We propose a model whereby TGFβ induces LINC00313 in order to regulate the expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and promotes cholangiocarcinogenesis.
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Grants
- Recurrent Funding Institut National de la Santé et de la Recherche Médicale (Inserm)
- Recurrent Funding,PhD felloship Université de Rennes 1 (University of Rennes 1)
- PhD fellowship Conseil Régional de Bretagne (Brittany Council)
- R22026NN,R21011NN Ligue Contre le Cancer (French League Against Cancer)
- R21043NN Fondation ARC pour la Recherche sur le Cancer (ARC)
- C18007NS,C20013NS,C20014NS INCa and ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé) dans le cadre du Plan cancer (Non-coding RNA in cancerology: fundamental to translational)
- R21095NN French Ministry of Health and the French National Cancer Institute, PRT-K20-136, CHU Rennes, CLCC Eugene Marquis, Rennes
- FIS PI18/01075,PI21/00922,CPII19/00008 Spanish Carlos III Health Institute (ISCIII) [(FIS PI18/01075, PI21/00922, and Miguel Servet Programme CPII19/00008) cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER)] and CIBERehd (ISCIII)
- HR17-00601 'la Caixa' Foundation ('la Caixa')
- EU/2019/AMMFt/001 AMMF-The Cholangiocarcinoma Charity
- 06119JB PSC Partners US and PSC Supports UK
- 825510/ESCALON European Union Horizon 2020 Research and Innovation Program
- EU TRANSCAN23-002-2023-129,INCa_18688 Institut National Du Cancer (INCa)
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Affiliation(s)
- Panagiotis Papoutsoglou
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
- ncRNA, Epigenetic and Genome Fluidity, CNRS UMR3244, Sorbonne University, PSL University, Institut Curie, Centre de Recherche, Paris, France
| | - Raphaël Pineau
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Raffaële Leroux
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Corentin Louis
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Anaïs L'Haridon
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Dominika Foretek
- ncRNA, Epigenetic and Genome Fluidity, CNRS UMR3244, Sorbonne University, PSL University, Institut Curie, Centre de Recherche, Paris, France
| | - Antonin Morillon
- ncRNA, Epigenetic and Genome Fluidity, CNRS UMR3244, Sorbonne University, PSL University, Institut Curie, Centre de Recherche, Paris, France
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, CIBERehd, Ikerbasque, San Sebastian, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - David Gilot
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
- Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, SE-48183, Mölndal, Sweden
| | - Marc Aubry
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France
| | - Cédric Coulouarn
- Inserm, Univ Rennes, OSS (Oncogenesis, Stress, Signaling) laboratory, UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, F-35042, Rennes, France.
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9
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Li J, Ma ZY, Cui YF, Cui YT, Dong XH, Wang YZ, Fu YY, Xue YD, Tong TT, Ding YZ, Zhu YM, Huang HJ, Zhao L, Lv HZ, Xiong LZ, Zhang K, Han YX, Ban T, Huo R. Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction. Acta Pharmacol Sin 2024; 45:517-530. [PMID: 37880339 PMCID: PMC10834533 DOI: 10.1038/s41401-023-01170-y] [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: 05/22/2023] [Accepted: 09/14/2023] [Indexed: 10/27/2023] Open
Abstract
Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na+ current (INa) and transient outward potassium current (Ito), as well as the expression of Nav1.5 and Kv4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and β-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI.
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Affiliation(s)
- Jing Li
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Zi-Yue Ma
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Yun-Feng Cui
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ying-Tao Cui
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Xian-Hui Dong
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Yong-Zhen Wang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Yu-Yang Fu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ya-Dong Xue
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ting-Ting Tong
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ying-Zi Ding
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ya-Mei Zhu
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Hai-Jun Huang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ling Zhao
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Hong-Zhao Lv
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Ling-Zhao Xiong
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Kai Zhang
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Yu-Xuan Han
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China
| | - Tao Ban
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China.
- Heilongjiang Academy of Medical Sciences, Baojian Road, Nangang District, Harbin, 150081, China.
| | - Rong Huo
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China.
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10
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Zhu Y, Kang A, Kuai Y, Guo Y, Miao X, Zhu L, Kong M, Li N. The chromatin remodeling protein BRG1 regulates HSC-myofibroblast differentiation and liver fibrosis. Cell Death Dis 2023; 14:826. [PMID: 38092723 PMCID: PMC10719330 DOI: 10.1038/s41419-023-06351-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 11/21/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023]
Abstract
Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Myofibroblasts, derived primarily from hepatic stellate cells (HSCs), are the effector of liver fibrosis. In the present study we investigated the mechanism by which Brahma-related gene 1 (BRG1, encoded by Smarca4) regulates HSC-myofibroblast transition and the implication in intervention against liver fibrosis. We report that BRG1 expression was elevated during HSC maturation in cell culture, in animal models, and in human cirrhotic liver biopsy specimens. HSC-specific deletion of BRG1 attenuated liver fibrosis in several different animal models. In addition, BRG1 ablation in myofibroblasts ameliorated liver fibrosis. RNA-seq identified IGFBP5 as a novel target for BRG1. Over-expression of IGFBP5 partially rescued the deficiency in myofibroblast activation when BRG1 was depleted. On the contrary, IGFBP5 knockdown suppressed HSC-myofibroblast transition in vitro and mollified liver fibrosis in mice. Mechanistically, IGFBP5 interacted with Bat3 to stabilize the Bat3-TβR complex and sustain TGF-β signaling. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of liver fibrosis by programming HSC-myofibroblast transition.
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Affiliation(s)
- Yuwen Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China
| | - Aoqi Kang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China
| | - Yameng Kuai
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China
| | - Yan Guo
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Xiulian Miao
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Li Zhu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Ming Kong
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
| | - Nan Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China.
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11
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Fu K, Dai S, Li Y, Ma C, Xue X, Zhang S, Wang C, Zhou H, Zhang Y, Li Y. The protective effect of forsythiaside A on 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestatic liver injury in mice: Based on targeted metabolomics and molecular biology technology. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166822. [PMID: 37523877 DOI: 10.1016/j.bbadis.2023.166822] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023]
Abstract
Cholestasis is a disorder of bile secretion and excretion caused by a variety of etiologies. At present, there is a lack of functional foods or drugs that can be used for intervention. Forsythiaside A (FTA) is a natural phytochemical component isolated from the medicinal plant Forsythia suspensa (Thunb.) Vahl, which has a significant hepatoprotective effect. In this study, we investigated whether FTA could alleviate liver injury induced by cholestasis. In vitro, FTA reversed the decrease in viability of human intrahepatic bile duct epithelial cells, the decrease in antioxidant enzymes (SOD1, CAT and GSH-Px), and cell apoptosis induced by lithocholic acid. In vivo, FTA protected mice from 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury, abnormal serum biochemical indexes, abnormal bile duct hyperplasia, and inflammatory infiltration. Furthermore, FTA treatment alleviated liver fibrosis by inhibiting collagen deposition and HSC activation. The metabonomic results showed that DDC-induced bile acid disorders in the liver and serum were reversed after FTA treatment, which may benefit from the activation of the FXR/BSEP axis. In addition, FTA treatment increased the levels of antioxidant enzymes in the serum and liver. Meanwhile, FTA treatment inhibited ROS and MDA levels and cleaved caspase 3 protein expression, thereby reducing DDC-induced hepatic oxidative stress and apoptosis. Further studies showed that the antioxidant effects of FTA were dependent on the activation of the BRG1/NRF2/HO-1 axis. In a word, FTA has a significant hepatoprotective effect on cholestatic liver injury, and can be further developed as a functional food or drug to prevent and treat cholestatic liver injury.
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Affiliation(s)
- Ke Fu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shu Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shenglin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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12
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Li N, Liu H, Xue Y, Zhu Q, Fan Z. The chromatin remodeling protein BRG1 contributes to liver ischemia-reperfusion injury by regulating NOXA expression. Life Sci 2023; 334:122235. [PMID: 37926300 DOI: 10.1016/j.lfs.2023.122235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
AIMS Hepatic ischemia-reperfusion injury (IRI) is a common complication secondary to liver transplantation. Extensive death of hepatocytes, typically in the form of apoptosis, is observed in and contributes to IRI. In the present study we investigated the role of BRG1 (encoded by Smarca4), a chromatin remodeling protein, in the pathogenesis of liver IRI focusing on the transcriptional mechanism and translational potential. METHODS Smarca4f/f mice were crossed to Alb-Cre mice to generate hepatocytes-specific BRG1 knockout mice (CKO). Alterations in cellular transcriptome were evaluated by RNA-seq. RESULTS BRG1 expression was up-regulated in liver tissues of mice subjected to I/R and in hepatocytes exposed to hypoxia-reoxygenation (H/R). Compared to wild type (WT) littermates, the BRG1 CKO mice displayed significant amelioration of liver injury following ischemia-reperfusion as evidenced by decreased ALT/AST levels and cell apoptosis. Primary hepatocytes isolated from the CKO mice were protected from H/R-induced apoptosis compared to those from the WT mice. RNA-seq analysis revealed phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) as a novel target for BRG1. Consistently, NOXA knockdown attenuated liver IRI in mice. More importantly, administration of a small-molecule BRG1 inhibitor (PFI-3) protected the mice from liver IRI. CONCLUSIONS Our data uncover a pivotal role for BRG1 in liver IRI and suggest that targeting BRG1 with small-molecule inhibitors can be considered as a reasonable therapeutic strategy.
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Affiliation(s)
- Nan Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Human Anatomy and Pathophysiology, Nanjing Medial University, Nanjing, China
| | - Hong Liu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Human Anatomy and Pathophysiology, Nanjing Medial University, Nanjing, China
| | - Yujia Xue
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Human Anatomy and Pathophysiology, Nanjing Medial University, Nanjing, China
| | - Qiang Zhu
- Department of General Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital, Nanjing, China.
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13
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Zhu Y, Guo Y, Xue Y, Zhou A, Chen Y, Chen Y, Miao X, Lv F. Targeting the chromatin remodeling protein BRG1 in liver fibrosis: Mechanism and translational potential. Life Sci 2023; 336:122221. [PMID: 39491218 DOI: 10.1016/j.lfs.2023.122221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
AIMS Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the interstitia. Hepatic stellate cells (HSCs) are considered the major source for ECM-producing myofibroblasts contributing to liver fibrosis. The molecular mechanism whereby HSC-myofibroblast transition is regulated remains incompletely understood. We investigated the involvement of BRG1, a chromatin remodeling protein, in this process. METHODS Rosa26-Smarca4 mice were crossed to Lrat-Cre mice to generate HSC-specific BRG1 transgenic mice. Liver fibrosis was induced by bile duct ligation (BDL) or injection with carbon tetrachloride (CCl4). RESULTS We report here that over-expression of BRG1 promoted HSC-myofibroblast transition in vitro. More importantly, the BRG1 transgenic mice displayed amplification of liver fibrogenesis, induced by BDL or CCl4 injection, compared to the wild type littermates. On the contrary, BRG1 inhibition by a small-molecule compound (PFI-3) attenuated HSC-myofibroblast transition in vitro and ameliorated liver fibrosis in a dose-dependent manner in mice. RNA-seq analysis showed that PFI-3 treatment preferentially influenced the expression of ECM genes in activated HSCs. CONCLUSION Our data provide strong evidence that BRG1 plays an important role in HSC-myofibroblast transition and suggest that targeting BRG1 could be considered as a reasonable strategy for the intervention of liver fibrosis.
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Affiliation(s)
- Yuwen Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yan Guo
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Yujia Xue
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Center for Experimental Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Anqi Zhou
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Ying Chen
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Yifei Chen
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Xiulian Miao
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China.
| | - Fangqiao Lv
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
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14
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Li S, Luo C, Chen S, Zhuang Y, Ji Y, Zeng Y, Zeng Y, He X, Xiao J, Wang H, Chen X, Long H, Peng F. Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis. J Transl Med 2023; 21:639. [PMID: 37726857 PMCID: PMC10510267 DOI: 10.1186/s12967-023-04469-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/21/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. METHODS The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. RESULTS BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway. CONCLUSION Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.
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Affiliation(s)
- Shuting Li
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Congwei Luo
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Sijia Chen
- Department of Nephrology and Rheumatology, The First Hospital of Changsha, Changsha, China
| | - Yiyi Zhuang
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yue Ji
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yiqun Zeng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yao Zeng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Xiaoyang He
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Jing Xiao
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Huizhen Wang
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Xiaowen Chen
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Haibo Long
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
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15
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Li N, Liu H, Xue Y, Xu Z, Miao X, Guo Y, Li Z, Fan Z, Xu Y. Targetable Brg1-CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking. EMBO Mol Med 2023; 15:e16592. [PMID: 36722664 PMCID: PMC9994483 DOI: 10.15252/emmm.202216592] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 02/02/2023] Open
Abstract
Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma-related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G+ neutrophils in the ALD mice. RNA-seq identified C-X-C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over-expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small-molecule compound PFI-3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof-of-concept for targeting the Brg1-CXCL14 axis in ALD intervention.
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Affiliation(s)
- Nan Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Hong Liu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Yujia Xue
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Zheng Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
| | - Xiulian Miao
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
| | - Yan Guo
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of PharmacologyChina Pharmaceutical UniversityNanjingChina
| | - Zhiwen Fan
- Department of PathologyNanjing Drum Tower Hospital Affiliated to Nanjing University Medical SchoolNanjingChina
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of PathophysiologyNanjing Medical UniversityNanjingChina
- Collage of Life Sciences and Institute of Biomedical Research, Liaocheng UniversityLiaochengChina
- State Key Laboratory of Natural Medicines, Department of PharmacologyChina Pharmaceutical UniversityNanjingChina
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16
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Liu Y, Wen D, Ho C, Yu L, Zheng D, O'Reilly S, Gao Y, Li Q, Zhang Y. Epigenetics as a versatile regulator of fibrosis. J Transl Med 2023; 21:164. [PMID: 36864460 PMCID: PMC9983257 DOI: 10.1186/s12967-023-04018-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/23/2023] [Indexed: 03/04/2023] Open
Abstract
Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications.
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Affiliation(s)
- Yangdan Liu
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Dongsheng Wen
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Chiakang Ho
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Li Yu
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | - Danning Zheng
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China
| | | | - Ya Gao
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Qingfeng Li
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
| | - Yifan Zhang
- Department of Plastic & Reconstructive Surgery, School of Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai, 200011, China.
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Zhang L, Sun T, Wu XY, Fei FM, Gao ZZ. Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma. World J Clin Cases 2022; 10:10501-10515. [PMID: 36312469 PMCID: PMC9602240 DOI: 10.12998/wjcc.v10.i29.10501] [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: 07/02/2022] [Revised: 08/14/2022] [Accepted: 08/30/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the mortality rate continues to rise each year. SMARCA4 expression has been associated with poor prognosis in various types of cancer; however, the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated.
AIM To explore the specific mechanism of action of SMARCA4 in HCC.
METHODS Herein, the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database. Furthermore, SMARCA4-high and -low groups were identified. Thereafter, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4, followed by construction of a SMARCA4-specific competing endogenous RNA (ceRNA) network using starBase database. The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.
RESULTS It was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC. Further, SMARCA4 expression was positively associated with tumor mutational burden, microsatellite stability, and immunotherapy efficacy. The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.
CONCLUSION The findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC. Moreover, a ceRNA network was detected, which was found to be correlated with poor prognosis in HCC. The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.
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Affiliation(s)
- Lei Zhang
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Ting Sun
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Xiao-Ye Wu
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Fa-Ming Fei
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
| | - Zhen-Zhen Gao
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
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18
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Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice. Nat Commun 2022; 13:5111. [PMID: 36042192 PMCID: PMC9427946 DOI: 10.1038/s41467-022-32575-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 08/08/2022] [Indexed: 11/21/2022] Open
Abstract
Excessive cholangiocyte expansion (ductular reaction) promotes liver disease progression, but the underlying mechanism is poorly understood. Here we identify biliary NF-κB-inducing kinase (NIK) as a pivotal regulator of ductular reaction. NIK is known to activate the noncanonical IKKα/NF-κB2 pathway and regulate lymphoid tissue development. We find that cholangiocyte NIK is upregulated in mice with cholestasis induced by bile duct ligation (BDL), 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), or α-naphtyl-isothiocyanate (ANIT). DDC, ANIT, or BDL induces ductular reaction, liver injury, inflammation, and fibrosis in mice. Cholangiocyte-specific deletion of NIK, but not IKKα, blunts these pathological alterations. NIK inhibitor treatment similarly ameliorates DDC-induced ductular reaction, liver injury, and fibrosis. Biliary NIK directly increases cholangiocyte proliferation while suppressing cholangiocyte death, and it also promotes secretion of cholangiokines from cholangiocytes. Cholangiokines stimulate liver macrophages and hepatic stellate cells, augmenting liver inflammation and fibrosis. These results unveil a NIK/ductular reaction axis and a NIK/cholangiokine axis that promote liver disease progression. Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
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19
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Lan T, Qian S, Tang C, Gao J. Role of Immune Cells in Biliary Repair. Front Immunol 2022; 13:866040. [PMID: 35432349 PMCID: PMC9005827 DOI: 10.3389/fimmu.2022.866040] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.
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Affiliation(s)
- Tian Lan
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuaijie Qian
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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20
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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21
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Shu Y, Xu Q, Xu Y, Tao Q, Shao M, Cao X, Chen Y, Wu Z, Chen M, Zhou Y, Zhou P, Shi Y, Bu H. Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling. Cell Death Dis 2021; 12:966. [PMID: 34667161 PMCID: PMC8526591 DOI: 10.1038/s41419-021-04263-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/26/2021] [Accepted: 10/06/2021] [Indexed: 02/05/2023]
Abstract
Numb, a stem cell fate determinant, acts as a tumor suppressor and is closely related to a wide variety of malignancies. Intrahepatic cholangiocarcinoma (iCCA) originates from hepatic progenitors (HPCs); however, the role of Numb in HPC malignant transformation and iCCA development is still unclear. A retrospective cohort study indicated that Numb was frequently decreased in tumor tissues and suggests poor prognosis in iCCA patients. Consistently, in a chemically induced iCCA mouse model, Numb was downregulated in tumor cells compared to normal cholangiocytes. In diet-induced chronic liver injury mouse models, Numb ablation significantly promoted histological impairment, HPC expansion, and tumorigenesis. Similarly, Numb silencing in cultured iCCA cells enhanced cell spheroid growth, invasion, metastasis, and the expression of stem cell markers. Mechanistically, Numb was found to bind to the Notch intracellular domain (NICD), and Numb ablation promoted Notch signaling; this effect was reversed when Notch signaling was blocked by γ-secretase inhibitor treatment. Our results suggested that loss of Numb plays an important role in promoting HPC expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers. Therapies targeting suppressed Numb are promising for the treatment of iCCA.
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Affiliation(s)
- Yuke Shu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yahong Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Tao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mingyang Shao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaoyue Cao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuwei Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenru Wu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Menglin Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongjie Zhou
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ping Zhou
- Department of Pathology, Sichuan Tumor Hospital, Chengdu, 610041, China
| | - Yujun Shi
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Hong Bu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
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22
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Gong W, Luo C, Peng F, Xiao J, Zeng Y, Yin B, Chen X, Li S, He X, Liu Y, Cao H, Xu J, Long H. Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis. Clin Sci (Lond) 2021; 135:1873-1895. [PMID: 34318888 PMCID: PMC8358963 DOI: 10.1042/cs20210447] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/09/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023]
Abstract
Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.
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Affiliation(s)
- Wangqiu Gong
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Congwei Luo
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Jing Xiao
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yiqun Zeng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Bohui Yin
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Xiaowen Chen
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Shuting Li
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Xiaoyang He
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yanxia Liu
- Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Huihui Cao
- Traditional Chinese Pharmacological Laboratory, Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jiangping Xu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Haibo Long
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
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