ZNF750调控p53信号通路抑制肺鳞癌恶性进展的分子机制研究

Lung squamous cell carcinoma is of high degree malignancy. ZNF750 is a newly discovered squamous cell lineage-specific tumor suppressor. The researchers reported the malignant phenotype of squamous cell carcinoma, both in oral squamous cell carcinoma and esophageal squamous cell carcinoma, were related to ZNF750’s abnormality. Our study found that low expression of ZNF750 in lung squamous cell carcinoma was associated with poor prognosis; upregulation of ZNF750 expression at the cellular level would slow down cell proliferation and migration; chromatin immunoprecipitation showed that ZNF750 binds to the TP53 genomic site and positive regulates TP53 expression, thereby activating p53 signaling pathway to act as a tumor suppressor. In the following study, this project intends to systematically investigate the molecular mechanism by which ZNF750 inhibits the malignant progression of lung squamous cell carcinoma by promoting the p53 signaling pathway at molecular, cell, mouse and clinical sample levels. In particular, we investigated the regulatory mechanisms of ZNF750 and other nuclear proteins on TP53 gene and related alternation of epigenetic markers include DNA methylation, and histone modification.

肺鳞癌是一种恶性程度较高的肺癌类型。ZNF750是新近发现的鳞癌谱系特异的肿瘤抑制因子，研究者们在口腔鳞癌和食管鳞癌中报道了ZNF750在鳞癌中的突变和低表达造成的恶性表型。我们的前期研究发现ZNF750在肺鳞癌组织中的低表达跟差的预后相关；在细胞水平ZNF750表达上调会使细胞增殖和迁移速度变慢；染色质免疫共沉淀结果显示ZNF750结合在TP53基因组位点上并正向调控TP53的表达，从而激活p53信号通路发挥抑癌功能。在接下去的研究中，本项目拟从分子、细胞、小鼠及临床样本层次，系统研究ZNF750调控p53信号通路抑制肺鳞癌恶性发展的分子机制，重点研究ZNF750和其他核蛋白在TP53基因区域的调控机制以及相关表观遗传变化。

锌指结构蛋白750（ZNF750）为鳞癌谱系特异的肿瘤抑制因子，本项目从分子、细胞、动物模型、临床组织标本这些层次系统地探究肺鳞癌恶性进展过程中 ZNF750的作用。我们的研究显示，ZNF750通过对生腱蛋白C（TNC）的转录调控，进而影响p53/ERK等信号通路，实现对鳞癌的抑制功能。本研究所提出的ZNF750-TNC轴为肺鳞癌的发生机制提供了新见解，并且有潜力在未来的研究中作为肺鳞癌治疗的干预的靶点。