卵巢癌腹水中STAT3-SLC3A2轴通过抑制肿瘤细胞铁死亡从而促进卵巢癌进程的作用及机制研究

卵巢癌是妇科肿瘤治疗的严峻难题，恶性腹水是其主要病理特征，与卵巢癌进程及预后不良显著相关。铁死亡是新型细胞死亡方式，研究表明铁死亡可能参与肿瘤进程但具体机制不明，因此研究铁死亡在腹水与卵巢癌进程中的作用可为临床寻找更有效治疗手段提供新的契机。申请人前期工作初步发现卵巢癌腹水上清可能通过IL-6\STAT3磷酸化通路抑制卵巢癌细胞铁死亡的发生，并由此首次鉴定出调控胱氨酸转运的铁死亡分子-SLC3A2。本研究将利用腹水与卵巢癌细胞共培养体系，通过质谱分析、ChIP、EMSA等技术从细胞、动物及临床标本三个水平明确腹水抑制卵巢癌细胞铁死亡的表型；探索SLC3A2与STAT3结合并被其转录调控，从而稳定XC-系统抑制铁死亡的机制；结合小鼠模型及临床病例明确STAT3与SLC3A2的相关性。本研究将揭示SLC3A2-STAT3通过抑制铁死亡促进卵巢癌进程的机制，为临床卵巢癌的治疗提供新的靶标。

Ferroptosis, is a newly defined nonapoptotic cell death type, characterized by aberrant iron metabolization and lipid peroxidation. Piles of data represent that ferroptosis is tightly related with types of tumors, and ferroptosis is a newly hot research field. The clinical threapy of ovarian cancer proceded very slowly because of high fatality and recurernce rate. Malignant ascites represents its pathological feature, and revelaing the relationship between ascites and progression of ovrian cancer might provide a new perspective to the clinical threapy. Our previous data showed that, the supernatant of ascites inhibit ferroptosis of ovarian cancer cell lines through IL-6\STAT3 pathway; high leve of STAT3 Ser727 presents upon the ascites treatment. Next, we screened out that STAT3 interacts with SLC3A2 through MS. Through in vivo and in vitro assay, we would clarify the phenoptype of ascites inhibits ferroptosis through IL-6\STAT3 pathway; explore the mechanisms of phrosphorylated-STAT3 transcriptional regulating SLC3A2; illustrate the relativity of phosphorylated-STAT3 and SLC3A2 through clinical samples and mouse model. In all, this project will shed light on the screening of ovraian cancer and provide new molecular target for clinical therapy.