HBx驱动甲胎蛋白表达调控重编程因子Oct4活性对肝细胞恶性转化的影响及其作用机制

Phosphorylated Oct4 is an important cell factor for inducing reprogramming of somatic cell. Recently, studies indicated that protein kinase-B(AKT) has a function to promote phosphorylation of Oct4; Our research found that alpha-fetoprotein(AFP) could activate AKT signaling, which implicated that AFP may has the capability to promote phosphorylation of Oct4. HBx plays an important role on hepatitis B virus inducing malignant transformation of liver cells, we demonstrated recently that HBx drove AFP expression preferentially to stimulated the transduction of AKT signaling, which displayed that expression of AFP is a critical factor for liver cell malignant transformation induced by HBx.Mature hepatocytes returning to pluripotent stem cells via reprogramming is the previous link to determine cell progression during the course of liver cell malignant transformation. We speculate that AFP may promote Oct4 phosphorylation by activating AKT to bring about the natural reprogramming of hepatocytes, which plays the decisive role in hepatocarcinogenesis. In this study, we will target normal liver cells and observe the preferential selectivity of HBx for AFP expression, at the same time we will explore the molecular mechanism of AFP regulating Oct4 phosphorylation followed by the induction of hepatocytes progression. This research will find that AFP has the role of regulating the hepatocytes reprogramming and has important scientific significance for knowing HBx early warning hepatocytes malignant transformation via driving expression of AFP.

Oct4磷酸化是诱导成体细胞重编程的重要活性细胞因子，近期研究证明蛋白激酶-B（AKT）能磷酸化Oct4；我们研究发现甲胎蛋白（AFP）可激活AKT信号，显示AFP有促进Oct4磷酸化的可能。在乙型肝炎病毒诱导肝细胞恶性转化的过程中，HBx发挥重要作用，我们新近证明HBx优先驱动AFP表达而激发AKT信号的传递，提示AFP表达是HBx诱发肝细胞恶性转化的关键因子，而在肝细胞恶性转化过程，成熟的肝细胞通过重编程回归多能干细胞是决定细胞恶变的先决环节。我们推测，AFP可能通过激活AKT促进Oct4磷酸化从而导致肝细胞的自然重编程，这对肝癌发生有决定性作用。本研究以正常肝细胞为对象，观察HBx对AFP表达的优先选择性,同时探索AFP调控Oct4磷酸化后促进肝细胞自然重编程从而诱导肝细胞恶变的分子机制。本项目研究结果对认识HBx通过驱动AFP表达预警肝细胞恶性转化有重要的科学意义。

Oct4 磷酸化是诱导成体细胞重编程的重要活性细胞因子，近期研究证明蛋白激酶-B（AKT）能磷酸化 Oct4；我们研究发现甲胎蛋白（AFP）可激活 AKT 信号，显示 AFP有促进 Oct4 磷酸化的可能。在乙型肝炎病毒诱导肝细胞恶性转化的过程中，HBx 发挥重要作用，我们新近证明 HBx 优先驱动 AFP 表达而激发 AKT 信号的传递，提示 AFP 表达是 HBx 诱发肝细胞恶性转化的关键因子，而在肝细胞恶性转化过程，成熟的肝细胞通过重编程回归多能干细胞是决定细胞恶变的先决环节。我们推测，AFP 可能通过激活 AKT 促进 Oct4 磷酸化从而导致肝细胞的自然重编程，这对肝癌发生有决定性作用。本研究以正常肝细胞为对象，观察HBx 对 AFP 表达的优先选择性,同时探索 AFP 调控 Oct4 磷酸化后促进肝细胞自然重编程从而诱导肝细胞恶变的分子机制。研究结果显示，乙型肝炎病毒-X蛋白（HBx）能优先诱导人正常肝细胞L-02和CHL的AFP和AFPR表达。AFP和AFPR的表达早于其它癌基因和转移相关基因的表达，证明AFP在诱导肝细胞恶性转化过程中起“先锋因子”的作用；发现AFP具有诱导肝细胞重编程因子Oct4、Klf4、Sox2和c-myc等因子的表达。AFP通过激活PI3K/AKT信号，促进肝癌干细胞的生成。肝癌细胞的胞浆内AFP对肝癌的形成和癌细胞的恶性生长具有正性调节作用，其能通过抑制凋亡信号的传递和激活生长信号对抗凋亡因子的诱导作用。结构生物学研究发现，AFP能与PTEN结合，研究发现AFP具有抑制PTEN活性的生物学功能，也就是AFP能激活PI3K/AKT信号传递。本项目研究结果对认识 HBx 通过驱动 AFP 表达预警肝细胞恶性转化有重要的科学意义。