Galectin 3-binding protein(LGALS3BP)depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1(TGF-β1)availability and inhibits hepatocarcinogenesis  

作　　者：Dae-Hwan Kim Minjeong Sung Myong-Suk Park Eun-Gene Sun Sumin Yoon Kyung Hyun Yoo Kamalakannan Radhakrishnan Sung Yun Jung Woo-Kyun Bae Sang-Hee Cho Ik-Joo Chung 

机构地区：[1]Department of Internal Medicine,Division of Hematology and Oncology,Chonnam National University Medical School,Hwasun,South Korea [2]Department of Internal Medicine,Division of Hematology and Oncology,Chonnam National University Hwasun Hospital,Hwasun,South Korea [3]Combinatorial Tumor Immunotherapy MRC Center,Chonnam National University Medical School,Hwasun,South Korea [4]National Immunotherapy Innovation Center,Hwasun,South Korea [5]BioMedical Sciences Graduate Program,Chonnam National University,Hwasun,South Korea [6]Department of Biological Science,SookmyungWomen’s University,Seoul,South Korea [7]Clinical Vaccine R&D Center,Chonnam National University,Hwasun,South Korea [8]Department of Biochemistry and Molecular Pharmacology,Baylor College of Medicine,Houston,Texas,USA

出　　处：《Cancer Communications》2024年第10期1106-1129,共24页癌症通讯（英文）

基　　金：Bio&Medical Technology Development Program of the National Research Foundation,Grant/Award Numbers:NRF-2020M3A9G3080281,NRF-2020R1A5A2031185;Korean Government。

摘　　要：Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.Methods:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and HCC.Multiple omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis.The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.Results:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive correlations.Stimulation of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1.Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 levels.LGALS3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton.The released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback loop.LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis.Moreover,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.Conclusion:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.

关 键 词：F-ACTIN FAK hepatic carcinogenesis IntegrinαV Interferonα JUNB LGALS3BP metabolic dysfuntion-associated steatohepatitis tensile force TGF-Β1 

分 类 号：R73[医药卫生—肿瘤]