URGCP介导HBV感染肝癌细胞的自噬性导致细胞耐药的分子机制研究

已有研究表明乙肝病毒(HBV)感染可诱导肝癌细胞发生自噬，导致肝癌细胞对化疗的敏感性降低，但其调控机制仍待阐明。前期我们发表文章证明HBV感染可诱导肝癌细胞的细胞增殖上调因子（URGCP）表达，并激活PI3K/AKT信号通路而促进细胞增殖。近期我们预实验显示URGCP可以抑制Beclin-1表达，诱导自噬，但该作用不依赖于I类PI3K/AKT信号通路，而可能与上调II类及III类PI3K自噬正调控因子相关，进而增强肝癌细胞对化疗药物的抵抗性。生物芯片分析显示miR-371是URGCP最为显著下调的microRNA，而miR-371的靶基因可直接调控PIK3C2A、PIK3C2B、PIK3C3及Beclin-1的表达。本项目将深入探讨URGCP通过下调miR-371而促进II类及III类PI3K的表达，进而诱导自噬促进化疗抵抗的分子机制，为HBV诱导肝癌细胞自噬而增强肝癌细胞耐药提供科学依据

Accumulating evidence has been showed that HBV can induce autophagy and then increase the chemotherapy resistant of human hepatocellular carcinoma. However, the underlying precise mechanism is largely unkonwn. In our recent published paper, we found that URGCP, a HBV up-regulated gene, overexpressed and promotes proliferation in HCC through PI3K/AKT signal pathway. Moreover, our preliminary studies observed that: 1) URGCP induced the autophagy of HCC cells, and thereby increase the chemotherapy sensitivity of HCC; 2）URGCP-induced autophagy was not correlated with class I, but II and III PI3K related signal pathway; 3）miR-371 was significantly down-regulated by ecotopic expression of URGCP and miR-371 could suppress the expression of PIK3C2A、PIK3C2B、PIK3C3 and Beclin-1. Therefore, our aim in current project is to systematically explore the mechanism underlying URGCP-induced chemoresistance and activation of autophagy through class I, II and III PI3K signaling in HCC, which would provide new insights into the therapeutic strategies for HCC.