GAS5与JAK/STAT通路构成正反馈环路促进甲状腺乳头状癌侵袭转移的机制研究

The incidence of thyroid papillary carcinoma (PTC) is growing faster than any other malignant tumors in recent years. Invasion and metastasis are the most important factors that related to a poor prognosis. It is of great theoretical and practical significance to study its mechanism in depth. Our previous study showed that the expression of long noncoding RNA GAS5 was significantly elevated in PTC and was involved in the invasion and metastasis of PTC. According to the bioinformatic analysis and previous study results, it was suggested that the mechanism might involve a positive regulatory feedback loop constituted by GAS5 and STRA6/JAK/STAT pathway. With this new discovery as the starting point, we aim to use molecular biological, tissue, cell and animal experiments to confirm that GAS5 can act as a competing endogenous RNA to increase the expression of STRA6 in PTC, and thus activates JAK/STAT pathway, and as a feedback to this pathway the transcription of GAS5 expression is upregualted. As a result, the invasion and metastasis of PTC cells are promoted. For the first time, GAS5 and STRA6/ JAK/STAT pathway are linked to each other to promote the invasion and metastasis of PTC as the research content, which will help to improve the understanding of the molecular mechanism of invasion and metastasis in PTC as well as provide new ideas for the diagnosis and treatment of PTC.

甲状腺乳头状癌（PTC）是近年来发病率增长最快的恶性肿瘤之一，侵袭转移是影响其预后的最重要因素，深入研究其机制有重要的理论和现实意义。申请人前期研究率先发现长链非编码RNA GAS5在PTC中表达异常升高，且参与促进PTC侵袭转移，根据生物信息学分析及前期研究结果推测其机制可能涉及GAS5与STRA6/JAK/STAT通路构成的正反馈调控环路。以这一新发现为切入点，我们拟利用分子生物学、组织、细胞和动物实验等证实GAS5可作为竞争性内源性RNA上调STRA6在PTC中的表达，进而激活JAK/STAT通路，而此通路又正反馈促进GAS5的转录表达，如此相互调控促进PTC侵袭和转移。本项目首次将GAS5与STRA6/JAK/STAT通路联系起来，以两者相互调控促进PTC侵袭转移作为研究内容，有助于完善PTC侵袭转移的分子机制研究，也为PTC的诊治提供新思路。

甲状腺乳头状癌（PTC）是最常见的甲状腺癌病理类型，也是近年来发病率增长最快的恶性肿瘤之一，侵袭转移是影响其预后的重要因素，深入研究其机制有重要的临床意义。本项目通过组织样本检测，细胞侵袭转移功能实验及qRT-PCR，Western Blot，荧光素酶报告基因实验等相关分子生物学方法明确了GAS5在PTC中表达异常升高，且具有促进PTC细胞侵袭转移的作用，初步阐明了GAS5通过miR-873-5p与STRA6构成竞争性内源性RNA关系，进而激活JAK/STAT3通路，最后通过STAT3/GAS5调控构成潜在的正反馈环路促进PTC细胞侵袭转移的机制。此外，课题组还发现了一种新的非编码RNA环状RNA hsa_circ_0137287，及基因融合(RET，ALK或NTRK1)，22q染色体拷贝数丢失以及T细胞受体克隆多样性与PTC侵袭转移相关。上述分子特征及GAS5，miR-873-5p，STRA6均可作为诊断PTC侵袭或转移的潜在标志物。本项目的研究结果可为PTC侵袭转移的机制研究及临床治疗提供新的思路和靶点。