Wnt/β-catenin信号通路介导TIP30调控喉癌上皮细胞间充质转换的研究

Epithelial- mesenchymal transitions (EMT) was the process of epithelial tumor cells gaining mesenchymal phenotype, and via EMT tumoer cells manifested more invasive and migratial charistic. TIP30 could regulate EMT in laryngeal carcinoma, enhanced the mRNA level of DKK1 and phosphorylation of β-catenin to rugulate the activity of Wnt/β-Catenin signaling pathway, which was associcated with EMT process in tumor cells. From above all, we made the hypoyhesis that it was Wnt/β-Catenin signaling pathway via which TIP30 reulated EMT in laryngeal carcinoma. To certificate the hypothesis, we would study the effect of Wnt/β-Catenin signaling pathway in the regulation of EMT induced by TIP30 in vivo and vitro. Chromatin immunoprecipitation (CHIP) and other related technic would be used to further explore the mechnasim of the regulation of Wnt/β-Catenin signaling pathway by TIP30. Our study will provide potential candidates for prognosis prediction and a new way for clinical treatment in larynx carcinoma.

喉癌转移，临床尚缺乏有效的治疗手段；上皮细胞间充质转换（EMT）使上皮表型的肿瘤细胞转换为间充质表型，增强了肿瘤的迁移及侵袭能力，与肿瘤的转移预后密切相关，但具体调控机制尚不完全清楚。申请人证实TIP30能调控喉癌等多种肿瘤细胞EMT水平，并发现TIP30能增强Wnt受体拮抗蛋白DKK-1的转录水平，影响β-catenin磷酸化水平，提示TIP30可调控Wnt/β-catenin通路活性。而Wnt/β-catenin通路与肿瘤EMT密切相关，据此推测TIP30可能通过抑制Wnt/β-catenin通路调控喉癌细胞EMT进程。为此，我们拟在细胞、组织、动物模型中研究Wnt/β-catenin通路在TIP30调控喉癌细胞EMT中的作用；利用CHIP等技术明确TIP30调控该通路的具体机制，旨在为喉癌预后评价提供可能的分子标志物，为寻找喉癌乃至其他恶性肿瘤的治疗新靶点提供新的理论及实验依据。

喉癌转移，临床尚缺乏有效的治疗手段；上皮细胞间充质转换（EMT）使上皮表型的肿瘤细胞转换为间充质表型，增强了肿瘤的迁移及侵袭能力，与肿瘤的转移预后密切相关，但具体调控机制尚不完全清楚。申请人通过奔课题已经证实了TIP30能调控喉癌EMT水平，同时TIP30可影响β-catenin磷酸化水平，调控Wnt/β-catenin的通路活性。进一步实验发现，DKK1是Tip30作用于Wnt/β-catenin通路的重要关键因子，TIP30可通过DKK1抑制Wnt/β-catenin通路从而调控喉癌细胞EMT进程。通过上述研究，我们发现了影响喉癌转移的新基因，并明确其分子作用机制，为喉癌的预后判断提供更加准确的分子标志物，也为寻找喉癌生物治疗新靶点提供新的理论及实验依据。