circ_0000817抑制 IGF2BP3/ GPER1轴逆转雌激素促甲状腺乳头状癌作用与机制研究

circ_0000817 was identified from our previous microarray data with the RNA-seq and it was significantly downregulated in female papillary thyroid carcinoma (PTC). Moreover, decreased circ_0000817 was negatively correlated with tumor size, tumor polycentricity and lymph node metastasis in PTC patients. In vitro experiments showed that overexpression of circ_0000817 could reverse the effect of estrogen on promoting occurrence and development of PTC. RNA pull-down, mass spectrometry, RIP experiments and bioinformatics analysis showed that circ_0000817 could bind to the RNA binding protein IGF2BP3, thereby reducing the mRNA stability of GPER1 which was the novel estrogen receptor. Therefore, we hypothesized that circ_0000817 could reverse the promoting effect of estrogen on PTC progression through inhibition of IGF2BP3/GPER1 axis. Study apply cell experiments and animal model to systemly evaluate the effect of circ_0000817 in reversal of estrogen-induced progression of PTC. From the perspectives of relationship between estrogen and gender-related incidence of PTC, our study will reveal the unknown function and mechanism of circRNA in the occurrence and development of PTC, which may provide novel biomakers and targets for PTC. If Study obtain success, it will open up a new horizon for the prevention and treatment of estrogen-related tumors, which has revolutionary innovation.

circ_0000817（简称CI）是申请人前期通过筛选获得一条在女性甲状腺乳头状癌（PTC）中低表达的circRNA，其表达与PTC的肿瘤大小、肿瘤多中心性及淋巴结转移负相关；体外实验表明CI可逆转雌激素促PTC的发生、发展。生物信息学分析及相关实验表明CI可与RNA结合蛋白IGF2BP3相结合，降低下游雌激素新型受体GPER1的mRNA稳定性。因此提出“CI通过诱捕结合蛋白IGF2BP3，在转录后减弱GPER1的mRNA稳定性，逆转雌激素促PTC发生、发展”的科学假说。本研究拟通过体外与体内实验，全面阐明CI抑制IGF2BP3/GPER1轴逆转雌激素促PTC发生、发展的分子机制。本课题从雌激素与PTC发病率性别差异视角，揭示circRNA在PTC发生、发展中的未知功能和机制，可为PTC诊治提供新线索与新靶标。研究若获成功，也可为其它雌激素相关肿瘤诊疗研究提供新思路。

甲状腺癌（TC）作为最常见且致死人数最多的内分泌恶性肿瘤，近年来已成为我国发病率增长最快的恶性肿瘤类型之一，其中甲状腺乳头状癌(PTC)是甲状腺癌中最为常见的病理类型且年轻女性好发。因此，研究PTC的潜在发病机制对TC的诊疗有着重大的临床意义。我们前期发现circ_0000817在PTC中存在差异表达，对PTC细胞相关细胞株和组织验证发现circ_0000817在PTC细胞和组织中低表达，且在女性PTC组织中表达更低。在甲状腺癌细胞K1中，circ_0000817过表达可抑制雌激素促PTC细胞增殖、迁移及侵袭能力。通过裸鼠成瘤实验，我们发现circ_0000817的过表达可抑制雌激素对PTC在小鼠肿瘤生长促进作用。此外，本研究还证实circ_0000817通过结合IGF2BP3从而降低下游GPER1的mRNA稳定性，进而抑制雌激素促PTC的发生、发展的作用。本研究的顺利实施，将丰富PTC发生、发展的理论研究，并可能为其诊疗提供新的靶标。