脂氧素受体ALX/FPR2对卵巢癌细胞干性的调控及机制研究

Cancer stem cells (CSCs) are a subpopulation of cancer cells with capabilities of self-renewal and differentiation. Ovarian CSCs are the root cause of growth, metastasis and recurrence of the ovarian cancer. The stemness maintenance of them is regulated by cytokines and chemokines and their receptors. The anti-inflammatory and proresolving mediator lipoxin A4 (LXA4), by activating its receptor ALX/FPR2, negatively regulates the inflammation and cancer related signalings such as STAT3 and NF-κB pathways, significantly inhibits the secretion of inflammatory factors, proliferation and metastasis of cancer cells, promotes cancer cell apoptosis. Our previous studies demonstrated the expression of ALX/FPR2 in ovarian CSCs. The stem cell markers Oct4 and CD133 were downregulated by LXA4, suggesting that ALX/FPR2 might directly regulates the stemness of CSCs. This study intends to elucidate the regulatory mechanisms of ALX/FPR2 on the self-renewal, differentiation, invasion and metastasis of ovarian CSCs. This study will enrich the theories of cancer pathophysiology and CSCs,and provide new clues for the development of anti-cancer therapeutic strategies.

肿瘤干细胞是具有自我更新能力和分化潜能的肿瘤细胞。卵巢癌干细胞是卵巢癌生长、转移和复发的根源，其干性的维持受细胞因子和趋化因子及其受体的调控。抗炎促消退介质脂氧素A4(LXA4)可通过活化其受体ALX/FPR2，负性调节STAT3和NF-κB等炎症及肿瘤发生相关的信号通路，显著抑制肿瘤细胞分泌炎症因子、增殖和转移，促进肿瘤细胞凋亡。我们预实验结果显示ALX/FPR2在卵巢癌干细胞表达，LXA4可下调干细胞标志Oct4和CD133的表达，提示ALX/FPR2可能直接参与肿瘤细胞干性的调控。本课题旨在系统阐明ALX/FPR2对卵巢癌干细胞自我更新、分化和侵袭转移的调控机制，为丰富肿瘤病理生理学和肿瘤干细胞理论做贡献，为抗癌治疗策略的制定提供新线索。

卵巢癌干细胞是卵巢癌生长、转移和复发的根源，调控卵巢癌干细胞的干性是潜在有效的提高卵巢癌患者存活率甚至根治肿瘤的关键。抗炎促消退脂质脂氧素A4及其受体ALX/FPR2已被证实可促进肿瘤细胞凋亡，抑制肿瘤细胞增殖和血管新生，但其是否调控肿瘤干细胞尚未见报道。本课题通过细胞水平、整体水平、干预实验等系统研究，明确了ALX/FPR2 对卵巢癌干细胞干性的影响，并初步阐明了具体机制；发现CD133+卵巢癌干细胞自分泌的CCL5可通过诱导卵巢癌非干细胞EMT化而促进其转移；发现脂氧素A4可抑制卵巢癌细胞的耐药性；阐明SP1-MRPs/12LOX轴介导卵巢癌细胞耐药的分子机制；发现卵巢癌干细胞铁死亡相关指标下调；通过Meta分析定量评估了Wnt-β-catenin通路重要调控AXIN2基因的rs2240308位点多态性与癌症（如卵巢癌）发生的危险性之间的相关性；在肿瘤免疫及免疫治疗方面也进行了探讨。本研究为防治卵巢癌转移提供新的分子靶点，将有助于丰富脂氧素的生物学功能和肿瘤干细胞特性理论，为肿瘤发生机制的阐明和抗癌治疗策略的制定提供新线索。项目资助在Cancer Research、Cell Reports等国际SCI期刊发表论文10篇，参编英文专著1部，参加AACR年会等国际国内学术会议10次，培养培养博士生6名，硕士生2名，各项支出基本与预算相符，剩余经费14.5447万元，剩余经费计划用于本项目研究后续支出。