The Gain-of-Function Mutation p53R248W Suppresses Cell Proliferation and Invasion of Oral Squamous Cell Carcinoma through the Down-Regulation of Keratin 17
The Gain-of-Function Mutation p53R248W Suppresses Cell Proliferation and Invasion of Oral Squamous Cell Carcinoma through the Down-Regulation of Keratin 17
复制标题
功能获得突变p53R248W通过下调角蛋白17抑制口腔鳞状细胞癌的细胞增殖和侵袭
DOI：
10.1016/j.ajpath.2020.11.011
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发表时间：
2021
影响因子：
6
通讯作者：
Muragaki Y.
中科院分区：
文献类型：
--
作者：
Enaka M;Nakanishi M;Muragaki Y.
角蛋白17（KRT 17）的表达促进了口腔鳞状细胞癌（OSCC）的增殖和侵袭，65%-85%的OSCC病例报告了TP 53的突变。我们研究了KRT 17表达与TP 53突变体的相关性。Ca 9 -22细胞表现出低KRT 17表达，其携带突变型p53（p53 R248 W），并且p53 R248 W敲低促进KRT 17表达。p53 R248 W基因敲低可促进Ca 9 -22细胞的迁移和侵袭活性。相反，在具有p53无义突变并表现出高KRT 17表达的HSC 3细胞中，p53 R248 W的过表达降低了KRT 17表达、细胞大小、增殖以及迁移和侵袭活性。此外，p53 R248 W还能显著抑制MMP 2 mRNA表达和酶活性。此外，s.c.并且原位异种移植物由表达p53 R248 W或p53 R248 Q的HSC 3细胞产生。由表达p53 R248 W的HSC 3细胞形成的肿瘤生长更慢，并且具有比来自对照或表达p53 R248 Q的HSC 3细胞的肿瘤更低的Ki-67指数。最后，接种表达p53 R248 W的HSC 3细胞的小鼠的存活率显著高于对照小鼠。这些结果表明，p53 R248 W突变体通过抑制KRT 17表达来抑制增殖和侵袭活性。我们认为p53 R248 W表达细胞的口腔鳞癌可能被归类为一种新的口腔鳞癌类型，具有良好的预后。
Keratin 17 (KRT17) expression promotes the proliferation and invasion of oral squamous cell carcinoma (OSCC), and mutations inTP53have been reported in 65% to 85% of OSCC cases. We studied the correlation between KRT17 expression andTP53mutants. Ca9-22 cells, which exhibit low KRT17 expression, carried mutant p53 (p53R248W) and p53R248W knockdown promoted KRT17 expression. p53R248W knockdown in Ca9-22 cells promoted migration and invasion activity. In contrast, in HSC3 cells, which have p53 nonsense mutations and exhibit high KRT17 expression, the overexpression of p53R248W decreased KRT17 expression, cell size, proliferation, and migration and invasion activities. In addition, p53R248W significantly suppressedMMP2mRNA expression and enzyme activity. Moreover, s.c. and orthotopic xenografts were generated from p53R248W- or p53R248Q-expressing HSC3 cells. Tumors formed from p53R248W-expressing HSC3 cells grew more slowly and had a lower Ki-67 index than those derived from the control or p53R248Q-expressing HSC3 cells. Finally, the survival rate of the mice inoculated with p53R248W-expressing HSC3 cells was significantly higher than that of the control mice. These results indicate that the p53R248W mutant suppresses proliferation and invasion activity through the suppression of KRT17 expression. We propose that OSCC with p53R248W-expressing cells may be classified as a new OSCC type that has a good prognosis.