肥胖相关基因TMEM18在子宫内膜癌中的表达调控及其作用机制研究

In recent years, with the increase of obesity and metabolic diseases, the incidence of endometrial carcinoma (EC) is also risen year by year. TMEM18 was the selected obesity-related gene by genome-wide association studies(GWAS). However, the role of this protein in obesity-related cancer is still undone. Our preliminary studies showed that the expression of TMEM18 was upregulated in endometrial carcinoma. In biological information science database GEO, estrogen could increased the expression of TMEM18. Thus, we propose a novel mechanism in EC, that function of TMEM18 in tumorigenesis and progression. This study is designed to exam the expression of TMEM18 in EC and analyze the association with clinicopathological parameters. Besides, through EC cell lines and orthotopic tumor model, we confirmed the regulation of estrogene in TMEM18 and the concrete regulating mechanism. At last, we will detecte biological function of TMEM18 in EC and the possible signaling.The study will enrich our knowledge on the relationship among obesity, estrogen and EC, and provide a solid experimental basis for further pre-clinical studies on TMEM18 as a potential molecular target for the therapy of EC.

近年来随着肥胖及代谢性疾病的增加，子宫内膜癌发病率也呈逐年增高的趋势。TMEM18是通过全基因组关联研究（GWAS）筛选出的肥胖相关基因，但在肥胖相关性肿瘤中作用尚未明确。预实验中TMEM18在内膜癌中表达升高，生物信息数据库GEO统计表明乳腺癌中雌激素促进TMEM18表达。由此我们提出肥胖相关基因TMEM18在内膜癌发生及进展过程中表达调控的新机制。本课题拟首先明确TMEM18在内膜癌中表达水平及与临床病理参数关系；其次通过体外细胞、内膜癌原位移植模型在体内外研究雌激素信号对TMEM18表达的影响及靶向调控机制；最后探讨TMEM18在内膜癌中生物学功能，检测相关的信号通路。该课题将丰富目前对肥胖、雌激素及内膜癌三者之间调控机制的认识，为临床前通过调控TMEM18实现针对雌激素下游靶基因的分子治疗提供理论依据。

近年来随着肥胖及代谢性疾病的增加，子宫内膜癌发病率也呈逐年增高的趋势。TMEM18是通过全基因组关联研究（GWAS）筛选出的肥胖相关基因，但在肥胖相关性肿瘤中作用尚未明确。本研究在正常子宫内膜、不典型增生子宫内膜及子宫内膜癌中通过免疫组织化学检测TMEM18表达水平，TMEM18在内膜癌中表达升高，且与ERα表达呈正相关，与临床分期呈正相关。在内膜癌细胞系ISK中用17β-雌二醇、ERα激动剂处理后，TMEM18表达水平升高，反之应用ERα抑制剂PPT后，TMEM18表达水平降低。构建子宫内膜癌原位移植瘤模型，给予长效缓释雌二醇处理后，免疫组化检测移植瘤TMEM18表达水平升高，瞬时转染ERα干扰质粒、过表达质粒，TMEM18表达水平分别降低、升高。构建稳定敲除及过表达TMEM18的细胞株，通过Transwell、划痕实验、CCK8实验证明TMEM18促进子宫内膜癌细胞增殖、侵袭及转移。在裸鼠荷瘤实验中，敲除TMEM18，肿瘤生长速度降低，4周后检测肿瘤体积及重量均低于对照组，免疫组化检测TMEM18及Ki67表达，Ki67表达水平降低。该研究阐明了肥胖相关基因TMEM18在子宫内膜癌发生进展中生物学功能，明确雌激素信号通路对TMEM18表达的调控，为子宫内膜癌的发病评估提供更完整的资料，为子宫内膜癌的诊断及治疗提供有效的理论依据。