循环来源的表观因素调控TERT作用机制与甲状腺乳头状癌风险分层的基础研究

The incidence of thyroid papillary carcinoma (PTC) increased significantly, precision diagnosis of recurrence and mortality risk is the key to individual treatment. The over expression of telomerase reverse transcriptase (TERT) is closely related to the development and prognosis of PTC. The TERT promoter mutation, which was previously identified by the applicant, has been included in the ATA guidelines as a new risk stratification factor for PTC, but the blood test target needs to be studied because the preoperative mutation test is depended on fine needle aspiration. In the preliminary study, we proved that lncRNA H19, miR-138 and TERT were directly targeted; in PTC, the expression of lncRNA H19 was positively correlated with TERT, meanwhile the expression of miR-138 was negatively correlated with TERT. Combined with the functional studies, it showed that lncRNA H19 acted as ceRNA, competed by sponge miR-138 and drived TERT expression, which due to the recurrence and mortality of PTC. This subject intends to study the circulatory epigenetics factors and mechanism of TERT from molecular, cellular, mouse and human tissue, blood levels. To explore the feasibility of combined testing of lncRNA H19 and miR-138 in Chinese population, avoiding the fine needle aspiration, and to diagnose the risk stratification of PTC by preoperative blood testing, providing a critical theoretical basis for PTC risk stratification diagnosis and treatment.

甲状腺乳头状癌（PTC）发病率显著上升，精准诊断复发死亡风险是个体化治疗的关键。端粒酶逆转录酶（TERT）高表达与PTC的发生发展及预后密切相关。申请人前期发现的TERT启动子突变已作为PTC新风险分层因素列入ATA最新指南，但因其术前检测依赖穿刺取材，血检靶标亟待研究。本课题前期研究发现lncRNA H19、miR-138和TERT直接靶向关系，PTC中lncRNA H19与TERT表达正相关，miR-138与TERT表达负相关，结合功能研究提示lncRNA H19作为ceRNA，通过海绵效应竞争miR-138驱动TERT异常表达，参与PTC复发死亡。本研究拟从分子、细胞、小鼠和人体组织、血液等多层次研究TERT循环来源的调控因素及作用途径。在我国人群探索lncRNA H19和miR-138联合检测，避免依赖穿刺，术前血检诊断PTC风险分层的可行性，为PTC风险分层诊疗提供关键理论基础。

甲状腺乳头状癌（PTC）发病率显著上升，精准诊断复发死亡风险是个体化治疗的关键。端粒酶逆转录酶（TERT）高表达与PTC的发生发展及预后密切相关。申请人前期发现的TERT启动子突变已作为PTC新风险分层因素列入ATA最新指南。本课题研究发现LncRNA FOXD2-AS1、miR-7-5p和TERT直接靶向关系，PTC中LncRNA FOXD2-AS1与TERT表达正相关，miR-7-5p与TERT表达负相关，LncRNA FOXD2-AS1作为ceRNA，通过海绵效应竞争miR-7-5p驱动TERT异常表达，参与PTC复发死亡;PTC死亡发生主要伴发肺转移，进一步研究揭示miR-424-5p通过抑制Hippo信号通路促进甲状腺癌失巢凋亡抗性和肺转移;并结合临床PTC高淋巴结转移特征，阐明Lnc MAPK8IP1P2通过吸附miR-146b-3p激活Hippo信号通路抑制甲状腺癌淋巴结转移。本研究从分子、细胞、动物模型和人体组织等多层次研究甲状腺乳头状癌（PTC）复发、肺转移、淋巴结转移的调控因素及作用途径。在我国人群探索lncRNA和miRNA联合检测，术前诊断PTC风险分层的可行性，为PTC的个体化预后评估和精准诊治策略，提供新的靶点及关键理论基础。本课题研究按计划执行完成，发表SCI 3篇，申请国家发表专利1项，培养博士、硕士研究生3名。本课题与意大利墨西拿大学病理学系、内分泌和微创外科 Gianlorenzo Dionigi教授联合研究，参加国内外学术合作交流6次，5次就课题成果大会发言。