HELQ在卵巢癌铂类耐药中的作用及分子机制研究

卵巢癌是预后最差的妇科恶性肿瘤，铂类耐药是其治疗难点。我们发现DNA损伤修复相关蛋白HELQ与卵巢癌铂类耐药密切相关，推测其参与DNA损伤修复促进铂类耐药表型。同时HELQ高表达耐药癌组织的间质成分明显增多，预示肿瘤微环境尤其肿瘤相关成纤维细胞（CAFs）活化可能维持其耐药表型的机制。本研究将先证实HELQ与DNA损伤修复蛋白RPA2相互作用，调控DNA损伤修复途径导致肿瘤耐药。再分离不同HELQ表达水平卵巢癌细胞外泌体，鉴定其差异蛋白后，通过体内、体外等多个层面，揭示高表达HELQ卵巢癌细胞通过外泌体引起CAFs异常活化，导致铂类耐药新机制。旨在阐明HELQ通过调控细胞本身及影响肿瘤微环境的双重手段，协同促进卵巢癌铂类耐药。

Ovarian cancer is the most common malignant tumor with a poor prognosis in gynaecology, platinum-related resistance is a difficult problem in clinical chemotherapy, and the mechanisms involved in platinum-related resistance require further study. HELQ, also known as POLQ-like helicase, is associated with DNA damage repair response. Our previous studies have shown that the high level of HELQ expression in ovarian cancer was significantly correlated with patients' response to platinum-related chemotherapy. Thus, we speculated that HELQ may promote the phenotype of platinum-related resistance in ovarian cancer via regulating DNA damage repair. Interestingly, the higher HELQ expression was in ovarian cancer tissues with platinum-related resistance, the more stroma components were in cancer tissues. We have presumed that tumor microenvironment, especially tumor-associated fibroblasts (CAFs), may be involved in maintaining drug-resistant phenotype. In the current research, we will confirm that HELQ interacts with RPA2 to regulate DNA damage repair leading to tumor resistance. On the other hand, we will collect the secreted exosomes from ovarian cancer cells with different levels of HELQ expression, and will screen the differentially expression profiles of exosome proteins. We will reveal that ovarian cancer cells with high expressed HELQ directly contribute to abnormal CAFs activation through exosomes secretion, leading to platinum-related resistance in ovarian cancer. The aim of this study is to clarify that HELQ promotes platinum-related resistance in ovarian cancer by regulating tumor cells themselves and also affecting tumor microenvironment synergistically.