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

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.