miR-151表达调控及关键靶基因在浆液性卵巢癌恶性表型中的作用

Serous ovarian carcinoma is the most common malignant ovarian cancer, and the 5 years survival rate is significantly lower than other types of ovarian cancer. The pathogenic mechanism of ovarian cancer still remains unknown， and the current clinical-pathologic staging method can not assess the prognosis of the patients accurately, and the individual therapy can not be implemented. We found in the early stduy that in highly malignant phenotype of ovarian cancer cell lines SK-G3,which had benn screened from a in vivo drug-resistant enrichment model, miR-151 expression was significantly increased. We also had the initial validation of its participation in the SK-G3 multiple malignant phenotype formation. Because microRNAs play a very important role in a variety of human diseases, including cancer, we want to clarify the relationship of transcription factors (which maybe the upstream regulatory factors) and miR-151, and screen the key downstream target genes of miR-151, by the use of CHIP, site-directed gene knockout technology (TALEN) and chip testing in this project. We will also test miR-151 expression and its significance in clinical specimens of serous ovarian carcinoma. The project will try to clarify the upstream regulation of miR-151, as well as its key functional target genes which play roles in the process of multidrug chemotherapy, tumor formation and metastasis, and to explain the occurrence and development mechnism of ovarian cancer. These studies will provide new clues for ovarian cancer research, and provide theoritic fundament of the molecular typing, molecular targets of intervention strategy of ovarian cancer.

浆液性卵巢癌恶性程度高，5年生存率极低，致病机制不明，现有的临床病理分期方法无法准确评估患者预后，患者个体化治疗无法实施。我们前期发现在通过体内耐药富集模型得到的高度恶性表型的卵巢癌细胞株SK-G3中，miR-151表达明显增高，并初步验证其参与了SK-G3的多种恶性表型的形成。鉴于microRNA在包括肿瘤在内的各种疾病中的重要作用，本项目拟利用CHIP、定点基因敲除TALEN技术和芯片检测，通过转录调节因子对miR-151的上游调控作用、miR-151下游关键靶基因的筛选和确定，以及miR-151在浆液性卵巢癌临床标本中的表达及意义等方面的研究，阐明miR151的上游调控、其功能靶基因对卵巢癌的化疗耐药、成瘤性和转移的作用机制，为解释浆液性卵巢癌的发生和发展提供新的线索，并为基于卵巢癌microRNA表达的分子分型、分子靶点的干预策略提供理论基础。

浆液性卵巢癌恶性程度高，5 年生存率极低，致病机制不明。在前期研究中，我们前期发现miR-151 表达在耐药细胞中明显增高，并初步验证其参与了 SK-G3 的多种恶性表型的形成。本研究对miR-151在患者石蜡切片中的表达情况与复发时间的关系进行了研究，发现miR-151表达水平与卵巢癌患者短期耐药及复发无明显相关性；细胞实验中我们发现，miR-151过表达后可以导致卵巢癌细胞侵袭转移能力增强，为了进一步阐明该机制，通过表达芯片分析和验证，发现miR-151通过其下游调控基因ACP1的表达影响细胞迁移与运动，并且ACP1与卵巢癌患者的预后有关，是预测卵巢癌预后的独立因素。本研究补充了卵巢癌转移的分子机制，并为卵巢癌预后预测和干预措施提供了新的靶点。