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

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

  • Cancer Commun (Lond). 2024 Jul 28. doi: 10.1002/cac2.12600.
Dae-Hwan Kim 1 2 3 4,  Minjeong Sung 1 2 3 4 5,  Myong-Suk Park 1 2 3 4,  Eun-Gene Sun 1 2 4,  Sumin Yoon 6,  Kyung Hyun Yoo 6,  Kamalakannan Radhakrishnan 7,  Sung Yun Jung 8,  Woo-Kyun Bae 1 2 3 4 5,  Sang-Hee Cho 1 2 3 4,  Ik-Joo Chung 1 2 3 4
Affiliations

Affiliations

  • 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, Sookmyung Women'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.
PMID: 39073023 DOI: 10.1002/cac2.12600
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.

Keywords

FAK; F‐actin; Integrin αV; Interferon α; JunB; LGALS3BP; TGF‐β1; hepatic carcinogenesis; metabolic dysfuntion‐associated steatohepatitis; tensile force.

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