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; Terence Kin Wah Lee

doi:10.1016/j.celrep.2016.04.019

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.

Affiliations

¹ State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, PRC; Department of Pathology, The University of Hong Kong, Hong Kong, PRC.
² State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, PRC; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, PRC.
³ Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PRC.
⁴ School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, PRC.
⁵ State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, PRC; Department of Pathology, The University of Hong Kong, Hong Kong, PRC. Electronic address: [email protected].
⁶ State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, PRC; Department of Pathology, The University of Hong Kong, Hong Kong, PRC. Electronic address: [email protected].

PMID: 27134167
DOI: 10.1016/j.celrep.2016.04.019

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