TNF-α促进肿瘤相关成纤维细胞分泌HGF调控c-Met/circ-CCNY信号通路介导肝癌进展的机制研究

肝癌是最常见的消化系统肿瘤之一，目前调控肝癌进展的分子机制远未阐明。我们前期研究证实，TNF-α参与肝癌进展并与患者预后不良相关。近期预实验研究显示，TNF-α促进肝癌相关成纤维细胞分泌HGF，后者与肝癌细胞表面c-Met结合，形成肝癌细胞-成纤维细胞互作网络；进一步环状RNA测序及生信分析提示，c-Met可能通过调控circ-CCNY及其下游STAT3/HIF-1α通路，促进肝癌细胞增殖和侵袭迁移。由此，我们提出以下科学问题：肝癌细胞分泌TNF-α促进肝癌相关成纤维细胞分泌HGF，HGF与肝癌细胞表面c-Met结合后激活circ-CCNY/STAT3/HIF-1α信号通路，从而发挥调控肝癌进展的功能。本项目将从组织、细胞和动物模型层面采用RNΑ-pull down、RIP、高通量测序等技术，通过体内外实验明确上述科学问题。项目的实施将为肝癌进展机制的阐明和治疗靶点的筛选提供新的科学依据。

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers in the digestive system. Up to date, the molecular mechanism of HCC progression still remains largely unknown. We have previously demonstrated that TNF-α was positively correlated to HCC progression and poor prognosis of patients with HCC, but its mechanism needs to be further explored. Here, we carried out preliminary experiment study and the results suggested that TNF-α increased both HGF expression and secretion in cancer-associated fibroblasts (CAF). In return, HGF significantly increased activation of c-Met in HCC cells. Furtherly, the circRNA genetic sequencing and bioinformatics analysis indicated that c-Met prompted HCC progression via regulating circ-CCNY and its downstream STAT3/HIF-1α signaling pathway. Thus, we hold the speculation that HCC cells express and secrete TNF-α to induce the secretion of HGF from cancer-associated fibroblasts. After that, HGF in turn binds to its receptor, c-Met, in the membrane of HCC cells. The activation of c-Met then regulates the expression of circ-CCNY and its downstream STAT3/HIF-1α signaling pathway, and finally prompts HCC cell proliferation, migration and invasion. The current study will systematically confirm the speculation proposed above by using techniques including RNΑ-pull down, RIP and genetic sequencing, etc. This study will help to clarify the molecular mechanism of HCC progression and provide potential therapeutic targets for HCC patients.