Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling

Cell Rep. 2016 May 10;15(6):1175-89. doi: 10.1016/j.celrep.2016.04.019. Epub 2016 Apr 28.

Abstract

Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC.

Keywords: FRA1; HEY1; cancer-associated fibroblasts (CAFs); hepatocyte growth factor (HGF); tumor-initiating cells (T-ICs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / metabolism
  • Cancer-Associated Fibroblasts / drug effects
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Separation
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Proto-Oncogene Proteins c-met / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Culture Media, Conditioned
  • HEY1 protein, human
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • fos-related antigen 1
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met