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

Eunice Yuen Ting Lau, Jessica Lo, Bowie Yik Ling Cheng, Mark Kin Fai Ma, Joyce Man Fong Lee, Johnson Kai Yu Ng, Stella Chai, Chi Ho Lin, Suk Ying Tsang, Stephanie Ma, Irene Oi Lin Ng, Kin Wah Lee

Research output: Journal article publicationJournal articleAcademic researchpeer-review

149 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1175-1189
Number of pages15
JournalCell Reports
Volume15
Issue number6
DOIs
Publication statusPublished - 10 May 2016

Keywords

  • Cancer-associated fibroblasts (CAFs)
  • FRA1
  • Hepatocyte growth factor (HGF)
  • HEY1
  • Tumor-initiating cells (T-ICs)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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