Snail-induced downregulation of deltaNp63 acquires invasive phenotype of human squamous cell carcinoma

蜗牛诱导的 deltaNp63 下调获得人类鳞状细胞癌的侵袭性表型

• 批准号: 17592085
• 负责人: HIGASHIKAWA Koichiro
• 金额: $ 2.18万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17592085/
• 关键词: Oral Cancer; EMT; Tumor Invasion and Metastasis; p63

p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by downregulation of p63 in human squamous cell carcinomas (SCCs). deltaNp63alpha is the predominantly expressed p63 isoform in SCC cells. deltaNp63 promoter activity required a C/EBP binding element and was reduced remarkably by Snail. Downregulation of deltaNp63alpha and reduction of C/EBPalpha were observed in EMT-phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of deltaNp63alpha blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail downregulates deltaNp63alpha, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by downregulation of deltaNp63alpha does not require downregulation of E-cadherin.

p63 是 p53 家族的成员，调节上皮结构形成中的关键事件，但 p63 在肿瘤中的作用尚不清楚。我们发现，在人类鳞状细胞癌（SCC）中，Snail 诱导的上皮间质转化（EMT）伴随着 p63 的下调。 deltaNp63alpha 是 SCC 细胞中主要表达的 p63 同工型。 deltaNp63 启动子活性需要 C/EBP 结合元件，并且被 Snail 显着降低。在 EMT 表型细胞中观察到 deltaNp63α 下调和 C/EBPα 减少，这些细胞在体外表现出侵袭活性。在 E-钙粘蛋白存在的情况下，细胞中 p63 的敲除增强了侵袭活性。相反，强制表达 deltaNp63alpha 会阻断具有 EMT 表型的细胞的侵袭活性。这些发现表明，Snail 下调 deltaNp63alpha，导致 SCC 获得侵袭性表型。由 deltaNp63alpha 下调引起的侵袭活动不需要 E-cadherin 下调。