Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling
Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling
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DOI：
10.1016/j.celrep.2016.04.019
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发表时间：
2016-05-10
期刊：
影响因子：
8.8
通讯作者：
Lee, Terence Kin Wah
中科院分区：
文献类型：
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作者：
Lau, Eunice Yuen Ting;Lo, Jessica;Lee, Terence Kin Wah
与正常干细胞一样，肿瘤起始细胞（T-IC）在肿瘤微环境中受到外部调控。由于HCC主要在肝硬化的背景下发展，其中存在活化成纤维细胞的富集，因此我们假设癌症相关成纤维细胞（CAF）将调节肝脏T-IC。我们发现α-SMA（+）CAF的存在与不良临床结局相关。CAF衍生的HGF以Erk 1，2依赖性方式通过激活FRA 1调节肝脏T-IC。进一步的功能分析确定HEY 1作为FRA 1的直接下游效应子。使用STAMNASH-HCC小鼠模型，我们发现HGF诱导的FRA 1激活与HCC的纤维化依赖性发展相关。因此，靶向CAF衍生的HGF介导的c-Met/FRA 1/HEY 1级联可能是治疗HCC的治疗策略。
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 alpha-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 STAMNASH-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.