PITPNC1在肝细胞癌浸润转移中的抑制作用及其分子机制

Hepatocellular carcinoma (HCC) is of high morbidity and mortality. Tumor invasion and metastasis are responsible for the poor prognosis of patients with HCC. However, the underlying mechanism of HCC progression remains elusive. Recently, we found that the PITPNC1 expression was decreased in HCC, and correlated with tumor metastasis and poor prognosis. The expression of PITPNC1 was inhibited by miR-92a in HCC cells. Further studies showed that overexpression of PITPNC1 induced the expression of p53 and its downstream effectors, to consequently promote the cell migration and invasion. Based on the findings, we assume that PITPNC1 is modulated by miR-92a and enhance tumor metastasis by targeting p53 signaling pathway in HCC. In this study, we aim to determine the expression of PITPNC1 and its clinical significance in HCC, to reveal how miR-92a modulates the expression of PITPNC1, and to disclose the mechanism of PITPNC1-mediated activation of p53 signaling, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only the reliable evidence of PITPNC1 involved in the malignant process of HCC, but also a promising therapeutic target.

肝细胞癌（HCC）的高度侵袭性和转移性是其恶性程度高、预后差的主要原因，但分子机制尚不清楚。我们前期观察到磷脂酰肌醇转移蛋白PITPNC1在HCC中低表达，与肿瘤转移及患者预后差相关；其表达受miR-92a抑制；过表达PITPNC1上调p53及其下游基因，抑制HCC细胞迁移。因此，我们提出PITPNC1受miR-92a调控，靶向p53通路抑制HCC浸润转移的假说。本项目拟利用多种细胞模型和裸鼠模型，采用一系列分子细胞生物学技术，在蛋白表达调控及细胞功能上，明确PITPNC1在HCC中的表达及其临床意义，揭示miR-92a抑制PITPNC1的作用机理，寻找PITPNC1激活p53信号通路的效应分子并探明其调控机制，阐述miR-92a/PITPNC1/p53信号轴抑制HCC细胞浸润转移的作用并解析其意义，为诠释HCC发生发展的分子机制和寻找HCC治疗新策略提供科学理论依据。

研究背景：肝细胞癌（HCC）的高度侵袭性和转移性是其恶性程度高、预后差的主要原因。研究表明磷脂酰肌醇转运蛋白(phosphatidylinositoltransferprotein，PITP)是一类脂质转运蛋白，在肿瘤发生发展过程中发挥重要作用。在本研究中，我们筛选出影响肝细胞癌侵袭转移的蛋白PITPNC1，并探索其在肝细胞癌发生发展中的生物学功能及临床应用价值。. 主要研究内容：通过制作HCC组织芯片，明确PITPNC1在HCC中的表达及其临床意义；利用多种细胞模型、裸鼠模型及分子细胞生物学技术，揭示miR-92a抑制PITPNC1的作用机理，寻找PITPNC1激活p53信号通路的效应分子并探明其调控机制。. 重要结果：我们发现PITPNC1在HCC中发挥抑癌作用。 PITPNC1在HCC中低表达，并与患者预后差及转移趋势相关。体外和体内实验均表明抑制PITPNC1会降低纤溶酶原激活物抑制剂1(PAI-1)的表达进而促进HCC迁移和侵袭，反之亦然。进一步研究表明，PITPNC1通过保护p53，减少其降解来增加PAI-1表达。最后，我们证明了miR-92a下调PITPNC1的表达并促进HCC细胞的迁移和侵袭。. 科学意义：我们的研究结果表明，PITPNC1在HCC中发挥抑癌作用，并通过miR-92a/PITPNC1/p53/PAI-1轴参与肿瘤转移，提示PITPNC1有望成为肝细胞癌的新预后标记及潜在治疗靶点。