PMEPA1 promotes androgen receptor-negative prostate cell proliferation through suppressing the Smad3/4-c-Myc-p21Cip1 signaling pathway
PMEPA1 promotes androgen receptor-negative prostate cell proliferation through suppressing the Smad3/4-c-Myc-p21Cip1 signaling pathway
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DOI：
10.1002/path.2834
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发表时间：
2011-04-01
影响因子：
7.3
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
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作者：
Liu, Rong;Zhou, Zhongmei;Chen, Ceshi
PMEPA 1基因已被证明可以抑制雄激素受体（AR）和TGF β信号通路，并在前列腺肿瘤中异常表达。然而，PMEPA 1在AR阴性前列腺癌中的作用和机制尚不清楚。在这里，我们证明，抑制PMEPA 1抑制AR阴性RWPE 1和PC-3前列腺细胞增殖，通过上调p21转录。此外，PMEPA 1过表达抑制p21表达并促进细胞增殖。PMEPA 1由TGF β诱导，作为负反馈环抑制Smad 3磷酸化和核转位;上调c-Myc;下调p21;并促进PC-3细胞增殖。PMEPA 1的功能依赖于其Smad 2/3结合基序。因此，Smad 3/4的缺失而非Smad 2的缺失阻断了PMEPA 1调节c-Myc和p21的功能。重要的是，PC-3中PMEPA 1的稳定消耗抑制异种移植物生长。最后，我们发现PMEPA 1在前列腺癌细胞系和肿瘤的一个子集中过表达。这些发现表明PMEPA 1可能通过p21促进AR阴性前列腺癌细胞增殖。版权所有. (C)2011年英国和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
The PMEPA1 gene has been shown to suppress the androgen receptor (AR) and TGF beta signaling pathways and is abnormally expressed in prostate tumours. However, the role and mechanism action of PMEPA1 in AR-negative prostate cancer are unclear. Here, we demonstrate that inhibition of PMEPA1 suppresses AR-negative RWPE1 and PC-3 prostate cell proliferation through up-regulating the p21 transcription. Additionally, PMEPA1 overexpression suppresses the p21 expression and promotes cell proliferation. PMEPA1 is induced by TGF beta as a negative feedback loop to suppress Smad3 phosphorylation and nuclear translocation; up-regulates c-Myc; down-regulates p21; and promotes PC-3 cell proliferation. The PMEPA1 functions depend on its Smad2/3 binding motif. Consistently, depletion of Smad3/4, but not Smad2, blocks PMEPA1's functions of regulating c-Myc and p21. Importantly, stable depletion of PMEPA1 in PC-3 inhibits xenograft growth. Finally, we found that PMEPA1 is overexpressed in a subset of prostate cancer cell lines and tumours. These findings suggest that PMEPA1 may promote AR-negative prostate cancer cell proliferation through p21. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.