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首页> 外文期刊>Cell cycle >Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model
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Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

机译：p21 / Cdkn1a的删除赋予小鼠前列腺模型转基因腺癌​​对抗前列腺癌的保护作用

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Cyclin-dependent kinase inhibitors (CDKIs) p21Cip1/Waf1 (p21) and p27Kip1 (p27) play a determining role in cell cycle progression by regulating CDK activity; however, p21 role in prostate cancer (PCa) is controversial. Whereas p21 upregulation by anticancer agents causes cell cycle arrest in various PCa cell lines, elevated p21 levels have been associated with higher Gleason score, poor survival and increased PCa recurrence. These conflicting findings suggest that more studies are needed to examine p21 role in PCa. Herein, employing genetic approach, transgenic mice harboring p21/Cdkn1a homozygous deletion (p21-/-) were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice to characterize in vivo consequences of p21 deletion on prostate tumorigenesis. Lower urogenital tract weight of p21-/-/TRAMP mice was significantly lower than those of p21+/-/TRAMP and TRAMP mice. Histopathology further supported these observations, showing less aggressiveness in prostates of p21 -/-/TRAMP. Furthermore, a significantly higher incidence of low-grade prostatic intraepithelial lesions (PIN) with a concomitant reduction in adenocarcinoma incidence was observed in p21-/-/TRAMP mice compared with TRAMP mice. In addition, whereas TRAMP mice showed the presence of poorly differentiated adenocarcinoma lesions, no such lesions were observed in p21/TRAMP transgenic mice. Specifically, there was a significant reduction in the severity of lesions in both p21-/-/TRAMP and p21 +/-/TRAMP mice compared with TRAMP mice. Together, our data showed that p21 deletion reduces prostate tumorigenesis by slowing-down progression of PIN (pre-malignant) to adenocarcinoma (malignant), suggesting that intact p21 expression is associated with PCa aggressiveness, while its decreased levels may in fact confer protection against prostate tumorigenesis.
机译：细胞周期蛋白依赖性激酶抑制剂（CDKI）p21Cip1 / Waf1（p21）和p27Kip1（p27）通过调节CDK活性在细胞周期进程中起决定性作用。然而，p21在前列腺癌（PCa）中的作用是有争议的。尽管抗癌药引起的p21上调导致各种PCa细胞系中的细胞周期停滞，但升高的p21水平与更高的格里森评分，不良的存活率和PCa复发率相关。这些矛盾的发现表明，需要更多的研究来检查p21在PCa中的作用。在本文中，采用遗传方法，将携带p21 / Cdkn1a纯合缺失（p21-/-）的转基因小鼠与小鼠前列腺（TRAMP）小鼠的转基因腺癌​​杂交，以表征p21缺失对前列腺肿瘤发生的体内影响。 p21-/-/ TRAMP小鼠的下泌尿生殖道重量明显低于p21 + /-/ TRAMP和TRAMP小鼠。组织病理学进一步支持了这些观察结果，显示p21-/-/ TRAMP在前列腺中的侵袭性较小。此外，与TRAMP小鼠相比，在p21-/-/ TRAMP小鼠中观察到低度前列腺上皮内病变（PIN）的发生率显着升高，同时伴随着腺癌发生率的降低。此外，虽然TRAMP小鼠显示出低分化腺癌病变的存在，但在p21 / TRAMP转基因小鼠中未观察到此类病变。具体而言，与TRAMP小鼠相比，p21-/-/ TRAMP和p21 + /-/ TRAMP小鼠的病变严重程度均明显降低。总之，我们的数据表明p21缺失通过减慢PIN（恶变前）发展为腺癌（恶性）的进程而减少了前列腺癌的发生，这表明完整的p21表达与PCa的侵袭性有关，而其降低的水平实际上可以赋予抗PCa的保护作用。前列腺癌发生。

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