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首页> 外文期刊>Cell cycle >Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype.
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Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype.

机译：p21 / Cip1和p27 / Kip1的下调会产生更具侵略性的前列腺癌表型。

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摘要

Roles of cyclin dependent kinase inhibitors, p21/Cip1 (p21) and p27/Kip1 (p27) in prostate cancer (PCa) progression is still not clear. Lower p27 protein expression in PCa tissues is often associated with poor prognosis, but prognostic significance of p21 is still controversial. Herein, we investigated the role of these molecules in determining PCa growth characteristics. We generated human PCa DU145 cell variants with knocked down levels of p21 (DU-p21) or p27 (DU-p27), or both (DUp21 + p27) via retroviral transduction of respective shRNAs and compared their various characteristics with empty vector-transduced DU145 (DU-EV) cells in vitro as well as in vivo. Knocking down either p21 or p27 did not show any significant change in doubling time, clonogenicity and cell cycle progression in DU145 cells, but simultaneous knock-down of both p21 and p27 significantly enhanced these parameters. In athymic mice, DU-p21 + p27 tumors showed higher growth rate than the comparable growth of DU-EV, DU-p21 and DU-p27tumors. Concurrently, DU-p21 + p27 tumors had significantly higher proliferation rate, showing 54% and 48% increase in proliferating cell nuclear antigen (PCNA) and Ki-67-positive cells, respectively, compared to DU-EV tumors. DU-p21 + p27 tumors also showed higher microvessel density and increased expression of vascular endothelial growth factor (VEGF). Proliferation and angiogenic status of DU-p21 and DU-p27 tumors was comparable to DU-EV tumors. Both in vitro and in vivo results implicate that p21 and p27 have compensatory roles in advanced prostate cancer cells, and ablation or downmodulation of both these molecules essentially enhances the aggressive prostate carcinoma phenotype.
机译：细胞周期蛋白依赖性激酶抑制剂p21 / Cip1（p21）和p27 / Kip1（p27）在前列腺癌（PCa）进展中的作用尚不清楚。 PCa组织中较低的p27蛋白表达通常与不良预后有关，但p21的预后意义仍存在争议。在本文中，我们研究了这些分子在确定PCa生长特征中的作用。我们通过各自的shRNA的逆转录病毒转导产生了人类PCa DU145细胞变异体，其水平分别降低了p21（DU-p21）或p27（DU-p27）或两者（DUp21 + p27）的水平，并将它们的各种特征与空载体转导的DU145进行了比较（DU-EV）细胞在体内和体外都有。敲除p21或p27在DU145细胞的倍增时间，克隆形成性和细胞周期进程中均未显示任何显着变化，但同时敲除p21和p27均显着增强了这些参数。在无胸腺小鼠中，DU-p21 + p27肿瘤的生长速度高于DU-EV，DU-p21和DU-p27肿瘤的可比生长速度。同时，DU-p21 + p27肿瘤的增殖率明显更高，与DU-EV肿瘤相比，增殖细胞核抗原（PCNA）和Ki-67阳性细胞分别增加了54％和48％。 DU-p21 + p27肿瘤还显示出更高的微血管密度和血管内皮生长因子（VEGF）的表达增加。 DU-p21和DU-p27肿瘤的增殖和血管生成状态与DU-EV肿瘤相当。体外和体内结果均暗示p21和p27在晚期前列腺癌细胞中具有补偿作用，并且这两种分子的消融或下调实质上增强了侵袭性前列腺癌的表型。

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