乙肝相关肝癌中HBx与突变型p53相互作用的机制与功能研究

Gene mutation and viral infection are two important factors in hepatocarcinogenesis. Recently, we found that: 1. the mutation rate of TP53 was higher in patients with HBV infection and the prognosis worse in the combination of HBV infection and TP53 mutation. 2. Through the use of gene expression microarray and in vitro experiment, the coefficient action of HBx and p53 mutation was preliminary confirmed and miR-375 was captured as the common downstream target. 3.HBx regulated cell function by directly interacting with mutation p53. So, we hypothesized that HBx interaction with mutation p53 had collaborative carcinogenic effect in HCC by regulation of miR-375. To confirm this hypothesis, we will: 1. consummate the study of relationship between HBV infection and driver gene mutation in vitro experiment and analysis of their correlation with clinical index, 2. study the relationship between HBx and mutation p53, 3. investigate the mechanism of how HBx and mutation p53 regulate miR-375 together, 4. research the carcinogenesis of miR-375 and its downstream in HCC, 5. Confirm the relative mechanism obtained above in mouse models and clinical specimens. This study will help to better elucidate the interaction of HBV infection and driver gene mutation and their cancerogenic mechanism in HCC.

乙肝病毒（HBV）感染与基因变异是肝癌发生的两个重要因素。我们近期发现：1）在肝癌中，HBV感染伴随较高的TP53突变率，且两者同时存在患者预后明显较差；2）通过表达谱芯片筛选及组织细胞验证，发现miR-375为HBx与突变型p53共同作用的下游靶点；3）在细胞中初步证实HBx与突变型p53可通过直接相互作用发挥功能。据此，我们推测HBx与突变型p53在肝癌中通过形成复合体共同调节miR-375表达进而发挥促癌作用。在此基础上，本课题将进一步扩大临床样本量，完善HBV感染与TP53突变的临床相关性分析及细胞功能学试验；研究HBx与突变型p53相互作用关系；阐明HBx与突变型p53共同调节miR-375表达的分子机制；并对miR-375的细胞生物学功能及其下游靶点通路进行探索；最后通过小鼠模型及临床样本回归验证上述机制。这将有助于阐明乙肝相关肝癌的发病机制，为探索临床诊疗新靶点提供理论依据。

乙肝病毒（HBV）感染是肝癌发生的重要因素之一。针对HBV相关肝癌发病机制，本课题通过以下三个途径进行阐释：1、HBx通过与ERα形成复合体调节LINC01352表达进而调控miR-135-APC活性在HBV相关肝癌中发挥作用 2、HBx通过调节PTPN13表达，进而调节IGF2BP1-c-MYC活性，从而在HBV相关肝癌中发挥作用 3、HBx通过与突变型TP53发挥协同作用，调节miR-425表达，通过外泌体途径在HBV相关肝癌中发挥作用。以上三个方面的研究将有助于阐明乙肝相关肝癌发病机制， 为探索肝癌临床诊疗新靶点提供理论依据。