SREBP1在子宫乳头状浆液性癌中的作用及机制研究

Sterol regulatory element binding protein 1 (SREBP1) transcription factor，the master regulator of lipid homeostasis, plays a critical role in cancer development and progression through lipid metabolic and microRNA pathways. In lipid metabolism, SREBP1 is regulated by multiple upstream elements, including growth factor receptor HER2, and its downstream targets p53 family proteins. In microRNA pathways, miR-33 are embedded in SREBPs genes, and act with their host genes to reciprocally regulate cholesterol homeostasis and fatty acid metabolism in a negative feedback loop. In addition, miR-33 cooperate with their host genes in regulating cell proliferation and cell cycle progression，which mechanism may related to lipid metabolism and p53-dependent apoptosis. Uterine papillary serous carcinoma (UPSC) is frequently characterized by overexpressing of p53 and HER2/neu genes. Thus, to explore the effects and underlying mechanism of SREBP1 in UPSC has become an exciting idea. We plan to investigate the biological function of SREBP1 in UPSC cell lines, the expression status in UPSC patients and its effects on lipid metabolism and expression levels of miR-33, to explore the molecular mechanisms and clinical value of SREBP1 in UPSC. Our study is expected to clarify the role of SREBP1 in UPSC progression, and opened up promising new avenues for the potential diagnosis and the development of therapeutics to treat UPSC.

SREBP1是脂代谢主控转录因子，通过脂代谢通路及小分子RNA途径参与调节肿瘤进展。在脂代谢通路中，SREBP1上游受生长因子受体HER2调节，下游调节转录因子p53家族蛋白。miR-33位于SREBPs的内含子中，协同SREBPs调节胆固醇的体内平衡及脂肪酸代谢的负反馈环路。此外，miR-33还协同调节细胞增殖和细胞周期进程，其机制除了与脂质代谢有关外，可能与p53介导的细胞凋亡有关。子宫乳头状浆液性癌（UPSC）作为特异性过表达p53及HER2的肿瘤，SREBP1在其发生发展中起到的作用及作用机制如何值得期待。本课题旨通过研究SREBP1在UPSC细胞株中的生物学功能、在UPSC患者中的表达情况、及对脂质代谢通路和miR-33表达水平的影响，探索其影响UPSC进展的分子机制和临床价值。本课题的完成，将有助于阐明UPSC进展过程中SREBP1所起的作用，也将为UPSC的治疗提供新的靶标。

SREBP1是脂质代谢主控转录因子，通过脂质代谢通路及小分子RNA途径参与调节肿瘤进展。在脂质代谢通路中，SREBP1上游受生长因子受体HER2调节，下游调节转录因子p53家族蛋白。miR-33位于SREBPs的内含子中，协同SREBPs调节胆固醇的体内平衡及脂肪酸代谢的负反馈环路。此外，miR-33还协同调节细胞增殖和细胞周期进程，其机制除了与脂质代谢有关外，可能与p53介导的细胞凋亡有关。子宫乳头状浆液性癌（UPSC）作为特异性过表达p53及HER2的肿瘤，SREBP1在其发生发展中起到的作用及作用机制如何值得期待。课题研究结果显示：（1）SREBP1为UPSC细胞株生长及转移所需要的关键蛋白。shSREBP1抑制细胞生长、克隆形成能力及SPEC-2细胞的体内生长，表明SREBP1为肿瘤生长所需要的关键蛋白; shSREBP1部分通过诱导细胞凋亡来抑制细胞增值并有效抑制细胞迁移。（2） SREBP1促进SPEC-2细胞中脂质合成相关基因的表达。敲低SREBP1后脂代谢相关基因FASN和SCD1蛋白表达下降， miR-33a/b水平下降，提示SREBP1可能通过miR-33抑制FASN和SCD1等脂代谢相关基因的表达; 荧光素酶报告基因分析显示SPEC-2细胞中激活SREBP1促进脂质合成相关基因FASN和mSCD1的表达; 基因芯片检测发现SREBP1对脂代谢及细胞周期相关通路有明显的调节作用。（3）SREBP1协同miRNA-33促进UPSC进展。SREBP1蛋白表达和活化与子宫内膜癌的进展呈正相关;. UPSC中P53相关碱基错配信号通路显著升高，p53基因在3'UTR区域有两个推定的miR-33结合位点发生了突变,miR-33可能与其宿主基因SREBPs通过 p53介导的细胞凋亡通路参与UPSC的肿瘤进展;UPSC中miR-30a-3p、miR-100、miR-146a、miR-320、miR-33a、miR-1207-5p水平有显著差异。本课题的完成，将有助于阐明UPSC进展过程中SREBP1所起的作用，也将为UPSC的治疗提供新的靶标。