Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma

• Published in: Biomedicine & pharmacotherapy Vol. 118; p. 109270
• Main Authors: Xie, Chengzhi, Liu, Guoxing, Li, Min, Fang, Yu, Qian, Ke, Tang, Yu, Wu, Xiaolong, Lei, Xiaohua, Li, Xiaocheng, Liu, Qiang, Liu, Gao, Liu, Jiefeng, Zhang, Yueming, Huang, Zhao, Hu, Zecheng, Cao, Zhenyu, Hu, Jixiong, Huang, Shengfu, Zhong, Dewu, Huang, Jiangsheng, Wu, Fangxiang, Wang, Jun, Mori, Masaki, Yamamoto, Hirofumi, Wang, Jianxin, Xu, Xundi
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.10.2019; Elsevier
• Subjects: Animals; Capsaicin - pharmacology; Carcinogenesis - drug effects; Carcinogenesis - pathology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - ultrastructure; Cell Line, Tumor; Cell Plasticity - drug effects; EMT; Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; HCC; Hepatocarcinogenesis; Humans; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - ultrastructure; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Ovol2; Transcription Factors - metabolism; TRPV Cation Channels - metabolism; TRPV1; Xenograft Model Antitumor Assays; Zeb1; Zinc Finger E-box-Binding Homeobox 1 - metabolism; AST; KO; H&E; HCC; ALT; DBI; TRPV1; AFP; DEN; ChIP; EMT; STR; Zeb1; DMEM; RSAT; TBA; hrEGF; Hepatocarcinogenesis; Zeb; TBIL; MET; WT; CHOL; Ovol2
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109270

[Display omitted] •TRPV1 shows targeting potential in hepatocellular carcinoma.•TRPV1 gives rise to phenotypic plasticity in hepatocarcinogenesis.•Tumor initiating cells and biliary cells were cellular origins in TRPV1 induced HCC.•TRPV 1 exert its role via transcription factors Ovol 2 and Zeb 1 mediated by SOX 10. The landscape of cellular plasticity and sources with relevant niche signals in hepatocellular carcinoma is still obscure. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is involved in a variety of malignancies and overexpressed in hepatocellular carcinoma (HCC). We have investigated the role of TRPV1 in HCC from different angles by various experimental techniques, such as in vivo and in vitro experiments, and by bioinformatics analysis of data from genetic models induced by diethylnitrosamine (DEN), mice samples and human HCC samples. We find that TRPV1 knockout promotes to hepatocarcinogenesis and deconstructs the portal triad adjacent to tumor border that is contributed by originations of tumor initiating cells and biliary cells. Epithelial to mesenchymal transition (EMT) is involved and transcription factors Ovol2 and Zeb1 coordinated with Sox 10 drive gene expression in the event which is also confirmed by the expression of these proteins in human HCC samples. Treatment with TRPV1 agonist Capsaicin inhibits the growth of HCC cells in xenograft models. Our findings demonstrate that TRPV1 is a potential therapeutic target in human HCC and exerts effects on cellular plasticity with modulation of Ovol2, Zeb1 and Sox10.