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 language | English |
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Pages (from-to) | 1175-1189 |
Number of pages | 15 |
Journal | Cell Reports |
Volume | 15 |
Issue number | 6 |
DOIs | |
Publication status | Published - 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)