乙肝病毒诱导IIA型磷脂酶A2表达正反馈促进原发性肝癌形成的机制研究

Hepatitis B virus (HBV) infection is a major incentive of primary hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. Phospholipase A2 group IIA (PLA2G2A) was reported to play an important role in tumorigenesis and development. In our previous work, we demonstrated that HBV upregulated the expression of PLA2G2A which in turn facilitates HBV replication, the expression of PLA2G2A in HBV associated liver cancer tissue is higher than in surrounding noncancerous tissue. Furthermore, PLA2G2A can promote cell colony formation, which suggested that HBV may positive feedback promote the formation of liver cancer by inducing the expression of PLA2G2A. However, there is no related report on how HBV induces the expression of PLA2G2A and what roles does PLA2G2A play in HBV-induced liver cancer. This project is planned to investigate the relationship between the expression levels of PLA2G2A and the staging and prognosis of HBV induced HCC, to explore the signaling pathway involved in the expression of PLA2G2A regulated by HBV and the ability of PLA2G2A to transform liver cells, and finally to trace the impact of PLA2G2A on HBV induced liver cancer formation and malignant phenotype by in vivo inhibition of PLA2G2A in HBV transgenic mice. Hopefully, this research will have great significance enriching the mechanisms of HBV carcinogenesis and is expected to provide theoretical basis for the molecular targeted therapy and prognostic monitoring for HBV related hepatocellular carcinoma.

乙肝病毒(HBV)感染是原发性肝癌(HCC)的主要诱因，但其致病机制不明。研究表明，磷脂酶A2-IIA（PLA2G2A）在肿瘤的发生和发展过程中发挥重要作用。前期工作，我们证实HBV上调PLA2G2A的表达；PLA2G2A促进HBV的复制；PLA2G2A在HBV相关肝癌组织中表达升高，并促进细胞集落的形成，提示HBV可能通过诱导PLA2G2A的表达正反馈促进肝癌的形成。但是HBV如何诱导PLA2G2A的表达及PLA2G2A在HBV致肝癌形成中的作用尚无相关报道。本项目拟从检测PLA2G2A表达与HBV相关肝癌病理分期及预后的相关性，HBV调控PLA2G2A表达的信号通路及其转化细胞的能力，在HBV转基因鼠体内抑制PLA2G2A表达后观察其对HBV致肝癌形成及恶性表型的影响等层面进行研究。该研究对丰富HBV致癌机理有重要意义，有望为HBV相关肝癌的分子靶向治疗及预后监测提供理论依据。

原发性肝癌(HCC)是世界上最常见的恶性肿瘤之一，其恶性程度高、生存期短。目前乙肝病毒（HBV）是公认的 HCC 主要诱因之一，HBV 感染机体后能够引发慢性乙型肝炎（CHB），最终发展成为肝纤维化（LC）和 HCC。HBV 编码的病毒蛋白在诱发肝癌形成过程中发挥了至关重要的作用，然而其分子机制不明。为深入探讨HBV致癌机理，前期工作，我们采用基因芯片筛选到HBV上调 PLA2G2A的表达；本项目拟检测PLA2G2A 表达与HBV相关肝癌病理分期及预后的相关性，HBV调控PLA2G2A表达的分子机制及其转化细胞的能力，PLA2G2A对肝癌形成及恶性表型的影响等层面进行研究。我们研究结果发现：（1）PLA2G2A能够在细胞水平促进HBV的复制；（2）HBV患者PLA2G2A血清水平升高，并且随着HBV疾病进程的发展，PLA2G2A 血清含量不断升高；（3）HBV通过激活PLA2G2A启动子活性，在转录和翻译水平上调PLA2G2A的表达；（4）pHBV1.3在HepG2细胞上调PLA2G2A mRNA和蛋白的表达；（5）PLA2G2A与HCC疾病分期及转移相关；（6）PLA2G2A在HBV相关肝癌组织中表达升高，并促进细胞集落的形成；（7）筛选到PLA2G2A相互作用蛋白C3、C4、CtBP2和SPINK1等；（8）证实了HBV在体内外抑制载脂蛋白C3和C4的合成和分泌；（9）证实了HBV通过其X基因上调PLA2G2相互作用蛋白CtBP2表达的的分子机制；（10）阐明了HBV与PLA2G2A之间正反馈调节促进肝癌形成的分子机制。本研究结果不仅丰富了 HBV的致癌机理，同时也为临床诊断和治疗乙肝相关肝癌及预后监测提供全新的思路。