RCAN1.4通过抑制CaN/NFAT信号通路阻遏肝癌转移的分子机制

肝癌是典型的富血管肿瘤，极易发生肝内和肝外转移。肝癌患者的预后差很大程度上是由于异常活跃的肿瘤血管生成和转移所致。然而当前对于肝癌的血管生成和转移机制仍知之甚少。RCAN1是CaN/NFAT信号通路的内源性抑制因子，据文献报道RCAN1可抑制血管内皮细胞对VEGF血管生成信号的响应。我们前期的研究结果表明，其选择剪接体RCAN1.4表达水平在肝癌组织显著低于配对的癌旁组织，且与肿瘤血管密度存在显著的负相关。在体外实验中，我们还发现RCAN1.4可以抑制肝癌细胞的迁移和侵袭。本课题计划采用HCC细胞、HCC荷瘤裸鼠和RCAN1.4肝特异性敲除鼠模型，并结合临床样本分析，探索RCAN1.4对肝癌肿瘤血管生成和转移的调控机制。通过确定介导RCAN1.4抑癌效应的关键靶分子，阐明RCAN1.4调控CaN/NFAT信号通路抑制肝癌转移的分子机理，期望为抗肿瘤血管生成治疗肝癌转移提供潜在靶点。

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic and extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, mechanisms underlying metastasis and angiogenesis in HCC remain to be revealed. RCAN1 is an endogenous regulator of Calcineurin/NFAT signaling activity, and recently is reported to suppress VEGF-mediated angiogenic signaling in endothelial cells. Our preliminary results showed that expression level of isoform RCAN1.4 was significantly down-regulated in tumor tissue compared with peritumoral tissue in HCC and its expression was inversely correlated with microvessel density in HCC samples. In addition, we found that RCAN1.4 could suppress migration and invasion of HCC in vitro. Therefore, we propose that RCAN1.4 may has antitumoral effects on HCC, which may be due to its ability to regulate tumor angiogenesis of HCC. This project aims to study regulatory effects of RCAN1.4 on the metastasis and tumor angiogenesis of HCC by HCC cells, xenograft mouse models of HCC, RCAN1.4 liver-specific knockout mice, and analysis for samples from HCC patients. We also attempt to identify target molecules that are involved in antitumoral effects of RCAN1.4, clarify the roles of CaN/NFAT signaling which is regulated by RCAN1.4, and provide a potential approach for antimetastatic therapy of HCC by anti-angiogenesis.