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

Biomed Pharmacother. 2019 Oct:118:109270. doi: 10.1016/j.biopha.2019.109270. Epub 2019 Aug 8.

Abstract

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.

Keywords: EMT; HCC; Hepatocarcinogenesis; Ovol2; TRPV1; Zeb1.

MeSH terms

  • 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
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • 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
  • TRPV Cation Channels / metabolism*
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • MOVO protein, mouse
  • Ovol2 protein, human
  • TRPV Cation Channels
  • Transcription Factors
  • Zinc Finger E-box-Binding Homeobox 1
  • Capsaicin