Tumor suppressor CLCA1 inhibits angiogenesis via TGFB1/SMAD/VEGF cascade and sensitizes hepatocellular carcinoma cells to Sorafenib

作者：Jin He, Fan Wu, Junfeng Li, Qianxi Deng, Jun Chen, Pengtao Li, Xianyao Jiang, Kun Yang, Shuman Xu, Zhongxiang Jiang, Zhongxiang Jiang, Xiaoqing Li, Zheng Jiang, Zheng Jiang · 发表于：Digestive and Liver Disease · 年份：2023 · DOI：10.1016/j.dld.2023.05.010 · 被引用次数：11 · 研究领域：TGF-β signaling in diseases、Angiogenesis and VEGF in Cancer、Liver physiology and pathology

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. Novel vascular-related therapeutic targets and prognostic markers remain urgently needed. AIMS: To investigate the role and mechanism of CLCA1 in hepatocellular carcinoma. METHODS: Immunofluorescence, Co-immunoprecipitation and rescue experiment were used to determine the specific mechanisms of CLCA1. Chemosensitivity assay was used to measure the impact of CLCA1 on Sorafenib. RESULTS: CLCA1 was dramatically downregulated in hepatocellular carcinoma cell lines and tissues. Ectopic expression of CLCA1 induced cell apoptosis and G0/G1 phase arrest while suppressed cell growth, inhibited migration and invasion, reversal of epithelial mesenchymal transition in vitro and reduced xenograft tumor growth in vivo. Mechanistically, CLCA1 could co-localize and interact with TGFB1, thereby suppressing HCC angiogenesis through the TGFB1/SMAD/VEGF signaling cascade in vitro and in vivo. Moreover, CLCA1 also enhanced the sensitivity of HCC cells to the first-line targeted therapy, Sorafenib. CONCLUSION: CLCA1 sensitizes HCC cells to Sorafenib and suppresses hepatocellular carcinoma angiogenesis through downregulating TGFB1 signaling cascade. This newly identified CLCA1 signaling pathway may help guide the anti-angiogenesis therapies for hepatocellular carcinoma. We also support the possibility of CLCA1 being a prognostic biomarker for hepatocellular carcinoma.