PKA/Akt-CREB5信号轴正向调控CAMs表达促进甲状腺乳头状癌淋巴结转移的作用及机制研究

The incidence of papillary thyroid carcinoma (PTC) is rapidly increasing and the rate of lymph node metastasis of PTC is high. The mechanism of lymph node metastasis in PTC is unclear. Our previous study found that CREB5 expression was elevated in PTC tissues with lymph node metastasis compared with PTC tissues without lymph node metastasis. And downregulation of CREB5 attenuated the invasive potential of PTC cells. GSEA analysis showed cell adhesion molecules (CAMs) pathway was significantly activated in PTC tissues with high expression of CREB5. These results suggest that CREB5 plays an important role in PTC lymph node metastasis, but its specific molecular mechanism needs further study. Based on our previous studies, we aimed to further study the role of CREB5 in PTC lymph node metastasis in vivo and in vitro by constructing lentiviral vectors, establishing popliteal lymph node metastasis model and lung metastasis model in nude mice; explore the roles and mechanisms of PKA/Akt-CREB5 signal axis on lymph node metastasis by regulating the expressions of cell adhesion molecules which increase the migratory and invasive abilities of PTC cells and promote the PTC lymph node metastasis. This study may provide a strategy for evaluating the risk of lymph node metastasis and find a promising drug therapeutic target in papillary thyroid carcinoma.

甲状腺乳头状癌(PTC)的发病率快速增长，淋巴结转移率较高。PTC发生淋巴结转移的机制尚未明确。我们前期研究发现CREB5在淋巴结转移组PTC组织中表达升高；在PTC细胞系中沉默CREB5的表达后，细胞的侵袭能力减弱；高表达CREB5的PTC组织中细胞黏附分子（CAMs）通路显著激活。上述结果提示CREB5在PTC淋巴结转移过程中发挥重要作用，但其具体分子机制需要进一步研究。本项目在已有研究基础上，通过构建慢病毒载体、建立裸鼠腘窝淋巴结转移模型及肺转移模型等进行体内外研究，明确CREB5在PTC淋巴结转移过程中的作用；运用ChIP、双荧光素酶报告基因实验等探索PKA/Akt-CREB5信号轴通过正向调控细胞黏附分子的表达，导致PTC细胞迁移侵袭能力增加，从而促进PTC淋巴结转移的作用及分子机制。该研究有望为评估PTC淋巴结转移风险提供依据，为发现潜在的药物靶标奠定基础。

甲状腺乳头状癌(PTC)的发病率快速增长，淋巴结转移率较高。本课题研究发现转录因子CREB5在PTC组织中表达升高（与癌旁组织相比），较高的CREB5表达与高淋巴结转移比率相关。在PTC细胞系中过表达CREB5后，PTC细胞系的增殖能力、集落形成能力、迁移侵袭能力增强；沉默CREB5则与之相反。机制方面，本课题通过TCGA数据库生信分析、CREB5染色质免疫共沉淀结合测序、以及甲状腺癌细胞系过表达CREB5之后的转录组测序等方法，发现CREB5通过作用于细胞黏附分子（CAMS）、JAK-STAT等信号通路，以及通过结合SIX4、ADAMTS14等基因的启动子区域影响其表达，最终促进人甲状腺乳头状癌的淋巴结转移。.该研究能够为评估PTC淋巴结转移风险提供依据，为发现潜在的药物靶标奠定基础。