ZBTB7A靶向Slug抑制鼻咽癌转移的机制研究

Distant metastasis are responsible for the poor prognosis of nasopharyngeal Carcinoma (NPC). However, the underlying mechanism remains elusive. Our chip data showed that the expression of ZBTB7A in NPC was decreased in high metastatic NPC cell line and lymph-node metastases and significantly correlated with distant metastasis-free survival (DMFS). Downregulation of ZBTB7A markedly induced the expression of Slug, and promoted cell migration and invasion. Collectively, we assume that ZBTB7A inhibits cell migration and invasion of NPC by targeting Slug. In this study, we aim to determine the expression of ZBTB7A and Slug and the relevant clinical significance in NPC, to unveil the mechanism of ZBTB7A-mediated regulation of Slug expression, and to reveal the role of ZBTB7A-Slug-E-cadherin signaling pathway in cell migration and invasion in NPC, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only solid evidence that ZBTB7A is involved in NPC progression, but also a promising therapeutic target in NPC.

远处转移是导致鼻咽癌预后差的主要因素，但其分子机制尚未明了。我们通过基因芯片观察到ZBTB7A在高转移鼻咽癌细胞及淋巴结转移灶中低表达，并与病人无远处转移生存率相关；细胞实验结果表明沉默ZBTB7A显著上调Slug表达，并促进鼻咽癌细胞迁移和侵袭；因此，我们提出ZBTB7A2靶向Slug，抑制鼻咽癌细胞转移的假说。本项目拟采用一系列分子细胞生物学和免疫学实验，利用多种细胞株和动物模型，在细胞功能及蛋白表达调控上，明确ZBTB7A和Slug在鼻咽癌中的表达及临床意义，揭示ZBTB7A调控Slug的作用机制，阐述ZBTB7A-Slug-E-cadherin通路在鼻咽癌细胞转移中的作用及其分子机制，从而获得ZBTB7A参与鼻咽癌转移调控的可靠证据，为寻找鼻咽癌治疗新靶点和诠释鼻咽癌发生发展的分子机制提供科学依据。

远处转移是导致鼻咽癌预后差的主要因素，但其分子机制尚未明了。我们通过基因芯片观察到ZBTB7A在高转移鼻咽癌细胞及淋巴结转移灶中低表达，并与病人无远处转移生存率相关；细胞实验结果表明沉默ZBTB7A显著促进鼻咽癌细胞迁移和侵袭；过表达ZBTB7A显著抑制鼻咽癌细胞迁移和侵袭；体内动物实验进一步证明ZBTB7A能够显著抑制裸鼠肺转移，调控机制方面，我们的研究表明敲低ZBTB7A显著上调Slug表达，相反，过表达ZBTB7A显著抑制Slug表达，因此，我们提出在鼻咽癌中，ZBTB7A2通过靶向抑制Slug表达，从而抑制鼻咽癌细胞转移，为寻找鼻咽癌治疗新靶点和诠释鼻咽癌发生发展的分子机制提供科学依据。依托本项目，已发表第一作者/通讯作者论文5 篇，其中SCI 收录期刊论文5篇，分别为：Frontiers in oncology (IF=6.244, 2篇)，Cancer Radiother (IF=1.018, 1篇)，BMC Gastroenterology (IF=3.067, 1篇)， BMC Cancer (IF=4.43, 1篇)。