上皮性卵巢癌紫杉醇耐药的新机制：Sp1-miR-181c-GRP78-PI3K/AKT信号通路

Taxol resistance is the major bottleneck in the treatment of epithelial ovarian cancer (EOC, a common gynecological malignant tumor), therefore it is very important to illustrate the mechanism. Our previous studies have shown that GRP78 (Glucose Regulated Protein 78) is related to taxol resistance in ovarian cancer and silenced GRP78 expression enhanced the sensitivity of EOC cells to taxol (increase EOC cells apoptosis). It has been reported that taxol resistance is regulated by PI3K/AKT signaling pathway, however the exact mechanism is poorly understood. We have affirmed that GRP78 gene contains the binding sites of miR-181c and predicted that Sp1 is the upstream transcription regulatory factor of miR-181c through luciferase reporter assay and molecular biology softwares. Therefore, we hypothesize that the “Sp1-miR-181c-GRP78-PI3K/AKT pathway” is the new mechanism of taxol resistance of epithelial ovarian cancer. Our study will take GRP78 as the important node protein and miR-181c as the new entry point. We plan to test our hypothesis through the techniques of molecular biological technique, morphological assay, luciferase reporter assay, chromatin immunoprecipitation and so on in human ovarian cancer tissue samples, nude mice model and cell lines. Our research will provide new theoretical basis and molecular target to achieve reversal of taxol resistance in clinical practice.

紫杉醇耐药是卵巢癌（妇科常见恶性肿瘤）治疗的主要瓶颈，阐明其机制至关重要。课题组前期研究发现GRP78与卵巢癌紫杉醇耐药相关，沉默GRP78能增强卵巢癌细胞对紫杉醇的敏感性（细胞凋亡增加）。有报道紫杉醇耐药受PI3K/AKT信号通路调控，但确切机制尚未完全阐明。我们通过生物学软件和荧光素酶报告基因技术已确认miR-181c与GRP78有靶向结合位点，并预测出Sp1是miR-181c的上游转录调控因子。因此，我们推测“Sp1-miR-181c-GRP78-PI3K/AKT”信号通路是调节卵巢癌耐药的新机制。为证实这一假说，本研究拟将GRP78作为重要节点蛋白，以miR-181c作为新切入点，通过人卵巢癌组织标本、荷瘤鼠模型、细胞系，应用分子生物学、形态学检测、荧光素酶报告基因、染色质免疫共沉淀等技术来加以求证。我们的研究成果，将为临床中实现逆转卵巢癌紫杉醇耐药提供理论依据和分子新靶点。