SERPINA11负向调控uPA抑制肝癌细胞的生长和转移

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal tumors in China. In this study, we have been committed to investigating SERPINA11 expression and function in HCC and have found SERPINA11 is a novel tumor suppressor gene. Downregulation of SERPINA11 was significantly associated with HCC metastasis. Functional study demonstrated that re-expression of SERPINA11 could inhibit tumor growth and metastasis in HCC. Negative correlation of SERPINA11 and uPA expression was shown in HCC cell lines. Moreover, We have found that SERPINA11 could bind to uPA inhibiting MEK/ERK pathways. We investigate the mechanisms of SERPINA11 suppress HCC growth and metastasis for the first time: SERPINA11 can bind to uPA and inhibit its activity in HCC, which may probably inhibit the activation of MMPs to degrade the ECM, Or suppress the ability of HCC growth and migration by inhibiting p38 MAPK、PI3K/AKT and ERK pathways. In this study, We will explore the SERPINA11 tumor suppress effect by COIP, site-specific mutation, Enzyme assay and tumor metastasis model in vivo. All these expected results would provide a theoretical basis for searching for novel biomarkers and designing new drugs in HCC.

肝癌是我国最常见的消化系统恶性肿瘤之一，在前期研究中发现SERPINA11低表达与肝癌的复发和转移相关，过表达SERPINA11抑制HCC细胞生长和转移，并且SERPINA11与uPA表达水平在HCC细胞中呈负相关。进一步实验证明了SERPINA11可以与uPA相互结合，抑制MEK/ERK1/2信号通路活性。由此，我们首次提出了SERPINA11抑制肝癌细胞生长和转移的新机制，即：SERPINA11通过与uPA直接作用并特异性抑制其活性从而抑制细胞外基质的降解；或通过抑制uPA下游信号通路p38MAPK、PI3K/AKT和ERK的活性抑制HCC的生长和转移。本项目拟进一步采用蛋白免疫共沉淀，定点突变作用位点，酶活性检测，动物体内转移瘤模型等方法，阐明SERPINA11负向调控uPA抑制肝癌细胞生长和转移的关键作用及其调控机制，为寻找肝癌新的预后指标及肝癌新药研发提供理依据。

肝细胞癌（hepatocellular carcinoma, HCC）是最常见的恶性肿瘤之一。HCC具有高发远处转移、低治愈率的特征，是严重威胁人类生命健康的恶性消化道肿瘤之一。SERPINA11是丝氨酸蛋白酶抑制剂家族（SERPINs）的一个成员，其在肝细胞癌中的功能和详细作用机制尚未有研究报道。因此，我们详细分析SERPIAN11在HCC中的表达及临床病理意义，研究了SERPIAN11的生物学功能，并探讨了SERPINA11促进肝细胞癌转移的分子机制。QPCR结果显示SERPINA11在肝癌组织及细胞株中的普遍表达下调。通过统计学分析SERPINA11在肿瘤组织的表达水平与临床病理特征的关系，发现SERPINA11低表达与患者肿瘤大小、包膜完整性以及复发和转移相关，Kaplan-Meier生存曲线分析发现，SERPINA11低表达患者的总生存期显著降低。单因素分析和多因素分析显示，SERPINA11表达水平是判断肝癌患者生存的独立预后因素。体内和体外的功能实验发现SERPINA11能够抑制HCC细胞的致瘤性和迁移侵袭能力、抑制HCC细胞尾静脉注射肺转移瘤的形成概率，提示它在肝细胞癌中具有抑制肿瘤转移的作用。在分子机制的研究中，发现SERPINA11蛋白与uPA蛋白相结合，SERPINA11在HCC细胞中的蛋白表达水平与uPA呈负相关，我们还发现SERPINA11可以在HCC中促进uPA蛋白的降解，抑制MEK/ERK信号通路激活来抑制HCC的转移。