Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis
Abstract 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...
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Wiley
2024-10-01
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| Series: | Cancer Communications |
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| Online Access: | https://doi.org/10.1002/cac2.12600 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dae‐Hwan Kim |
| collection | DOAJ |
| description | Abstract 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, transposase‐accessible 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 interferon α in 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 integrin αV, 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. |
| format | Article |
| id | doaj-art-c3b44f6f6e2b460c8e2108f0bb0c616e |
| institution | OA Journals |
| issn | 2523-3548 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
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| series | Cancer Communications |
| spelling | doaj-art-c3b44f6f6e2b460c8e2108f0bb0c616e2025-08-20T01:47:48ZengWileyCancer Communications2523-35482024-10-0144101106112910.1002/cac2.12600Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesisDae‐Hwan Kim0Minjeong Sung1Myong‐Suk Park2Eun‐Gene Sun3Sumin Yoon4Kyung Hyun Yoo5Kamalakannan Radhakrishnan6Sung Yun Jung7Woo‐Kyun Bae8Sang‐Hee Cho9Ik‐Joo Chung10Department of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Biological Science Sookmyung Women's University Seoul South KoreaDepartment of Biological Science Sookmyung Women's University Seoul South KoreaClinical Vaccine R&D Center Chonnam National University Hwasun South KoreaDepartment of Biochemistry and Molecular Pharmacology Baylor College of Medicine Houston Texas USADepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaDepartment of Internal Medicine Division of Hematology and Oncology Chonnam National University Medical School Hwasun South KoreaAbstract 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, transposase‐accessible 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 interferon α in 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 integrin αV, 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.https://doi.org/10.1002/cac2.12600F‐actinFAKhepatic carcinogenesisIntegrin αVInterferon αJunB |
| spellingShingle | 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 Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis Cancer Communications F‐actin FAK hepatic carcinogenesis Integrin αV Interferon α JunB |
| title | Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis |
| title_full | Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis |
| title_fullStr | Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis |
| title_full_unstemmed | Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis |
| title_short | Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis |
| title_sort | galectin 3 binding protein lgals3bp depletion attenuates hepatic fibrosis by reducing transforming growth factor β1 tgf β1 availability and inhibits hepatocarcinogenesis |
| topic | F‐actin FAK hepatic carcinogenesis Integrin αV Interferon α JunB |
| url | https://doi.org/10.1002/cac2.12600 |
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