TNFAIP8调控上皮性卵巢癌细胞自噬参与铂类耐药的机制研究

项目名称： TNFAIP8调控上皮性卵巢癌细胞自噬参与铂类耐药的机制研究

项目编号： No.81502225

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘天伯

作者单位： 哈尔滨医科大学

项目金额： 18万元

中文摘要： 铂类耐药是上皮性卵巢癌治疗的主要瓶颈之一。我们研究发现肿瘤坏死因子α诱导蛋白8（TNFAIP8）与上皮性卵巢癌铂类耐药具有相关性，沉默TNFAIP8能有效抑制细胞增殖、增强细胞对顺铂的敏感性、上调该细胞自噬相关蛋白Beclin1、LC3II的表达。然而，TNFAIP8调节自噬参与上皮性卵巢癌铂类耐药的机制，国内外尚未见报道。鉴于PI3K/AKT/mTOR信号通路通过抑制肿瘤细胞自噬参与化疗耐药，我们提出假说：TNFAIP8通过活化PI3K/AKT/mTOR信号通路抑制上皮性卵巢癌细胞自噬从而促进铂类耐药。为证实这一假说，我们拟通过体内外实验来明确TNFAIP8与上皮性卵巢癌细胞增殖、化疗敏感性的相关性。用顺铂诱导肿瘤细胞耐药，通过自噬、mTOR、PI3K/AKT抑制剂干预，进一步说明TNFAIP8促进上皮性卵巢癌细胞铂类耐药的分子机制，为临床中实现逆转上皮性卵巢癌铂类耐药提供理论依据。

中文关键词： 卵巢肿瘤；肿瘤坏死因子α诱导蛋白8；；铂类耐药；自噬；哺乳动物雷帕霉素靶蛋白

英文摘要： Platinum resistance is one of the major bottlenecks in epithelial ovarian cancer (EOC) treatment. Our studies have shown that tumor necrosis factor α–induced protein 8 (TNFAIP8) overexpressed in EOC and was related to platinum resistance. Furthermore, we have demonstrated that down-regulation of TNFAIP8 expression would inhibit EOC cells proliferation，enhance the sensitivity of EOC cells to cisplatin and increase the expression of autophagy-related protein Beclin1 and LC3II. However, the mechanism that TNFAIP8 regulates autophagy involved in platinum-resistant EOC has not been reported at home and abroad. With respect to that PI3K/AKT/mTOR signaling pathway involves in resistance to chemotherapy by inhibiting the autophagy of tumor cell, we propose the hypothesis: TNFAIP8 could inhibit EOC cell autophagy to promote platinum resistance by activating PI3K/AKT/mTOR signaling pathway. To confirm this hypothesis, we intend to elaborate the relationship of TNFAIP8 with EOC cell proliferation and with chemosensitivity in vivo and in vitro experiments, respectively. Inducing tumor cell resistance to cisplatin, we further explain the molecular mechanism that TNFAIP8 promote EOC platinum resistance by using inhibitor intervention of autophagy, mTOR and PI3K/AKT. We should provide theoretical basis to achieving reversal of EOC platinum resistance in clinical practice.

英文关键词： ovarian cancer;TNFAIP8;platinum resistance;autophagy;mTOR