title: Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.
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.
authors.affiliation: 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.
authors.forename: Eunice Yuen Ting
authors.initials: EY
authors.lastname: Lau
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lo
authors.affiliation: 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.
authors.forename: Bowie Yik Ling
authors.initials: BY
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Mark Kin Fai
authors.initials: MK
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Joyce Man Fong
authors.initials: JM
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Johnson Kai Yu
authors.initials: JK
authors.lastname: Ng
authors.affiliation: 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.
authors.forename: Stella
authors.initials: S
authors.lastname: Chai
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PRC.
authors.forename: Chi Ho
authors.initials: CH
authors.lastname: Lin
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, PRC.
authors.forename: Suk Ying
authors.initials: SY
authors.lastname: Tsang
authors.affiliation: 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.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
authors.affiliation: 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: iolng@hku.hk.
authors.forename: Irene Oi Lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: 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: terence.kw.lee@polyu.edu.hk.
authors.forename: Terence Kin Wah
authors.initials: TK
authors.lastname: Lee
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002469:Cell Separation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000099169:Fos-Related Antigen 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D017077:Culture Media, Conditioned; D017228:Hepatocyte Growth Factor; D016760:Proto-Oncogene Proteins c-fos; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger; D000099169:Fos-Related Antigen 1; C485631:HEY1 protein, human
keywords: FRA1; HEY1; cancer-associated fibroblasts (CAFs); hepatocyte growth factor (HGF); tumor-initiating cells (T-ICs)