干细胞因子Sall4在顺铂治疗卵巢癌疗效监测和耐药复发中的临床价值和机制研究

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers and approximately 85% of the patients will experience relapse after treatment. The chromosomal region, 20q12-13, is commonly amplified in ovarian cancer and we hypothesize that human Sall4 gene, located on chromosome 20q13.2, is an important candidate gene that plays an essential role in ovarian cancer initiation. We have found that Sall4 over-expression is seen in more than 20% of ovarian cancer and it is significantly increased in the middle stage of malignant transformation model. Down-regulation of Sall4 expression by shRNA leads to apoptosis and growth retardation. However, whether Sall4 is involved in the resistance of cisplatin, one of the first-line chemotherapies for ovarian cancer, or can be a potential monitoring target for cisplatin efficacy have not been reported yet. In this study, we will assess the level of Sall4 in newly diagnosed and relapsed patients by analyzing their peripheral blood and tumor tissue. The clinical value of Sall4 in monitoring cisplatin efficacy and the risk of relapse will be further elucidated by the well-established circulating tumor cells detecting platform in our lab. In addition, we will dissect the mechanism of Sall4 in the cisplatin resistance in cell lines and mouse models by both gain of function and loss of function studies, combined with cytotoxicity assays, and explore the association of Sall4 with Notch pathway. We will also verify the potential of Sall4 as a therapeutic target by using a specific Sall4 peptide in the treatment of ovarian cancer.

卵巢癌致死率在妇科肿瘤中高居首位，约85%的患者治疗后经历复发。染色体20q12-q13区域扩增常见于卵巢癌，而干细胞因子Sall4可能是该区域扩增的靶基因。我们的前期研究表明Sall4过表达于超20%的卵巢癌患者，在卵巢癌恶性转化中期即显著升高，下调Sall4表达水平导致细胞凋亡和生长阻滞。但Sall4是否参与到卵巢癌化疗药物顺铂的耐药及能否作为其疗效监测靶点尚未见报道。我们拟从临床角度，检测初诊和复发患者外周血和肿瘤组织中Sall4的表达，并借助自身建立的CTCs分离鉴定平台动态研究CTCs中Sall4表达在卵巢癌顺铂疗效和耐药复发中的监测价值，以期寻找新的监测指标；进一步，在细胞和动物水平通过Sall4功能缺失和获得性实验，结合细胞毒性实验和分子生物学技术，探究Sall4在卵巢癌顺铂耐药中的作用机制；最后通过制备靶向Sall4的多肽探究Sall4作为顺铂耐药卵巢癌治疗靶点的可行性。