乙肝病毒x蛋白(HBx)调控microRNAs(miR-193b)的机制及其对乙肝相关肝癌肿瘤学特性影响的研究

HBx蛋白是乙肝病毒致癌的重要因素，可通过诱导抑癌基因启动子区域高甲基化来抑制该基因表达。我们的前期研究发现HBx可上调DNA甲基转移酶家族（DNMTs）的表达，同时去甲基化处理后可恢复某些被HBx抑制的miRNAs表达，如miR-193b。进一步研究发现miR-193b与肝癌的肿瘤生物学特性有密切关系，且其表达水平与患者预后明显相关。因此，我们提出HBx通过DNA甲基化调控miRNAs表达而发挥其致癌作用的假设。本课题将先在肝癌细胞模型中以miR-193b为切入点，研究HBx是如何通过影响DNMTs调控microRNAs表达，并通过进一步研究miR-193b的功能，以揭示HBx调控miRNAs从而影响乙肝相关肝癌肿瘤学特性的机制，并在肝癌临床标本中加以回归验证。本研究有助于阐明HBx在肝癌中的作用，为寻找新的防治措施提供新的理论依据。

Hepatitis B virus x protein(HBx) was proved to be a key factor in hepatocarcinogenesis process caused by HBV. Previous investigations suggested that inhibition of some tumor suppressor genes by HBx via inducing hypermethylation of CpG islands in the promoter region could be a crucial step in the development of hepatocellular carcinoma(HCC). In our previous study, HBx was shown to be able to up-regulate DNMTs and down-regulate some miRNAs,such as miR-193b, which could be restored after demethylation treatment in HepG2/HBx cell lines. And also, further research revealed that miR-193b is closely related with oncogenic activities of HCC and the prognosis of patients with liver cancer surgery. So we hypothesized that it is by inducing hypermethylation of promoter region that HBx regulated the expression of miRNAs. In the present study, we will take miR-193b as a key point to verify the hypothesis as stated above in HBx+/- cell lines and hepatocellular carcinoma tissues,explore its specific mechanism in vitro,and also we will find possible downstream targets of miR-193b ,such as Mcl-1, ZBTB5, c-Kit and so on, and research its effects on biological characteristics of hepatocarcinoma, that may help to elucidate the mechanism of hepatocarcinogenesis and provide new therapeutic targets for HBV-related HCC.