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

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-07-28 DOI:10.1002/cac2.12600
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
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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.

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通过减少转化生长因子-β1(TGF-β1)的可用性和抑制肝癌的发生,消耗凝集素 3 结合蛋白(LGALS3BP)可减轻肝纤维化。
背景:Galectin 3结合蛋白(LGALS3BP)血清水平的升高已被用于评估肝纤维化阶段和肝细胞癌(HCC)的严重程度。考虑到转化生长因子-β1(TGF-β1)在这些疾病的发生中的关键作用,本研究对 LGALS3BP 调节 TGF-β1 信号通路的假设进行了检验:方法:分析了代谢功能障碍相关性脂肪性肝炎(MASH)和HCC患者中LGALS3BP和TGFB1的表达水平。研究人员采用RNA测序、转座酶可访问染色质测序分析和液相色谱-串联质谱蛋白质组学等多种omics技术来确定LGALS3BP-TGF-β1轴的调控机制。在条件性LGALS3BP-knockin和LGALS3BP-knockout小鼠中研究了LGALS3BP改变TGF-β1信号传导的影响:结果:在MASH和HCC患者中,LGALS3BP和TGFB1的水平呈正相关。HCC 细胞中的炎性细胞因子干扰素 α 对 LGALS3BP 的刺激或肝细胞中 LGALS3BP 的异位过表达促进了 TGFB1 的表达水平。在肝细胞特异性LGALS3BP敲除小鼠的肝脏中观察到纤维化加重,TGFB1水平升高。LGALS3BP直接与整合素αV结合并组装,整合素αV是将活性TGF-β1从细胞外潜伏复合物与重新排列的F-肌动蛋白细胞骨架中释放出来所需的整合介质。释放的 TGF-β1 激活了 JunB 转录因子,而 JunB 又促进了 TGF-β1 的正反馈循环。肝细胞中 LGALS3BP 的缺失下调了 TGF-β1 信号传导和 CCl4 诱导的纤维化。此外,LGALS3BP缺失通过限制纤维化TGF-β1的可用性,阻碍了肝癌的发生:结论:LGALS3BP通过控制TGF-β1信号通路,在肝纤维化和肝癌发生过程中发挥着重要作用,因此是治疗TGF-β1相关疾病的理想靶点。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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