Nrf2-Keap1信号通路与自噬在卵巢癌顺铂耐药中的串话

Nrf2作为转录因子广泛存在于全身多器官。Nrf2 - Keap1信号通路除了在维持细胞氧化还原方面起重要作用外，还参与肿瘤耐药，但其机制不明。我们的预实验结果提示 Nrf2的表达与卵巢癌细胞对顺铂的敏感性有关，而对顺铂耐药的卵巢癌细胞自噬活性增强，此外，抑制Nrf2mRNA的表达会改变细胞的自噬活性。为此，我们提出假说：Nrf2可能通过与自噬的串话共同参与了卵巢癌的顺铂耐药机制。 为验证这一假说，我们将通过人卵巢癌细胞系和裸小鼠人卵巢癌原位移植瘤模型，采用分子标记、免疫印迹、腺病毒载体转染、RNA干扰、电镜以及高通量染色质免疫共沉淀芯片等手段， 从分子、细胞、及动物整体水平等多方面探讨 Nrf2与自噬在卵巢癌耐药中的作用、及其相互影响，深入揭示Nrf2-Keap1信号通路在卵巢癌铂类耐药中的作用，并全面评价自噬在卵巢癌铂类耐药中的动态改变，丰富顺铂耐药机制，为卵巢癌化疗提供潜在的新靶点。

Nrf2 is a transcription factor that is ubiquitously expressed in all human organs. Nrf2-Keap1-ARE signaling pathway not only plays an important role in maintaining cellular oxidoreduction and homeostasis, but is involved in chemo-resistance during cancer therapy. The underlining mechanism is still unknown. Our preliminary data showed the expression of Nrf2 in ovarian cancer cells related to chemo-resistance, while the level of autophagy increased with cisplatin treatment, moreover, decreased mRNA level of Nrf2 changed the autophagy level in ovarian cancer cells. Based on these findings, we propose our hypothesis, Nrf2 and autophagy may be involved in the cisplatin-induced ovarian cancer cells chemo-resistance by its crosstalk. To testify this hypothesis, several kinds of ovarian cancer cells and an orthotopic implantation nude mouse model of human epithelial ovarian cancer are to be established, molecular markers, western blot, adenovirus transfection, electron microscope and high throughout chromatin immune precipitation are to be used to explore the role of Nrf2 and autophagy , and its crosstalk in ovarian cancer cisplatin-resistance. The mechanism is to be elaborated from the angle of molecular, cellular and animal whole body level. Thus will not only provide new targets for ovarian chemotherapy, but present theoretical basis for the autophagy-induced cancer cell death as well as Nrf2-related chemosensitivity are to be acted as novel cancer therapeutic model.