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

  • Dig Liver Dis. 2023 May 23;S1590-8658(23)00618-7. doi: 10.1016/j.dld.2023.05.010.
Jin He  1 ,  Fan Wu  1 ,  Junfeng Li  1 ,  Qianxi Deng  1 ,  Jun Chen  1 ,  Pengtao Li  2 ,  Xianyao Jiang  3 ,  Kun Yang  1 ,  Shuman Xu  1 ,  Zhongxiang Jiang  1 ,  Xiaoqing Li  1 ,  Zheng Jiang  4
Affiliations
  • 1. Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 2. Department of Neurosurgery, Peking Union Medical College Hospital, Beijing 100044, China.
  • 3. Department of Otorhinolaryngology Head and Neck Surgery, Hainan General Hospital, Haikou 570100, China.
  • 4. Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
PMID: 37230858 DOI: 10.1016/j.dld.2023.05.010
Abstract

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.

Keywords
Anti-angiogenesis; Chemosensitivity; Gene expression; Prognostic.
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