乙肝病毒X蛋白通过血管生成素核转位影响tRNA半分子富集的作用机制

乙肝病毒(HBV)的慢性感染是肝细胞癌(HCC)发生的主要风险因素。乙肝病毒X蛋白(HBx)在HBV诱发HCC发生的炎癌转化过程中起重要作用与其促进肝癌新生血管生成有关，机制不清。血管生成素(ANG)具有促进肿瘤细胞增殖和促进新生血管生成的双重作用，该作用是否通过其剪切生成的tRNA半分子(tiRNA)实现？目前知之甚少。我们前期发现tiRNA在HCC组织中富集显著减少，而在癌旁肝炎组织中富集明显，这种变化可能与HBx和ANG亚细胞定位存在相关性。进一步发现HBx能促进ANG核转位。这些提示HBx可能通过刺激ANG核转位所诱发的tiRNA富集抑制和rRNA生物发生失调实现对肝癌新生血管生成和癌细胞增殖的调控。本课题将以HBx、HBV全基因组稳转肝癌细胞系为模型结合临床资料验证这一提示，以其理解tiRNA富集是细胞应对不利生存环境的一种天然自我保护机制，并为抗肝癌血管生成提供新的分子靶点。

HBV infection leads to wide spectrum of liver disease ranging from acute to chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). The viral transactivator HBx plays a pivotal role in the initiation and maintenance of hepatic inflammatory processes through interactions with components of the HCC microenviroment, which is attribute to the promotion of angiogenesis by HBx, and the mechanism is not clear. Angiogenin (ANG) has a dual role in promoting the proliferation of tumor cells and promoting angiogenesis of new blood vessels , but whether the effect is realized through tRNA halves produced by ANG shearing tRNA is very little known. We found that tiRNA was abundant in hepatitis tissue of HBV, however, the abundant of tiRNA in cancer tissue of HCC was significantly decreased, which could be correlated with the subcellular expression localization of HBx and ANG. Further study demonstrated that HBx can promote nuclear translocation of ANG. These findings suggest that HBx may regulate the angiogenesis and cell proliferation of HCC by inhibiting the tiRNA abundant whcih was induced by nuclear translocation of ANG and making the disorder of rRNA biogenesis. To verify this hypothesis, the vitro models based on human hepatoma cell lines transfected with HBV whole-genome and HBx respectively were used in this study, which are benefit for understanding that tiRNA abundant is an innate defence mechanism to prevent oncogenic translation and providing a molecular target for anti angiogenesis in the treatment of HCC.