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

Cell Reports

卷:15

Chi Ho Lin¹  Suk Ying Tsang²  Johnson Kai Yu Ng³  Bowie Yik Ling Cheng³  Irene Oi Lin Ng³  Stella Chai³  Eunice Yuen Ting Lau³  Stephanie Ma³  Terence Kin Wah Lee³  Jessica Lo³  Joyce Man Fong Lee³  Mark Kin Fai Ma³ 

[1] Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, PRC;

[2] School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, PRC;

[3] State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, PRC;

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

DOI  :  10.1016/j.celrep.2016.04.019

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown