Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer
Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer
复制标题
DOI：
10.1038/sj.onc.1210963
复制
发表时间：
2008-05-08
期刊：
影响因子：
8
通讯作者：
Leung, H. Y.
中科院分区：
文献类型：
--
作者：
McCracken, S. R. C.;Ramsay, A.;Leung, H. Y.
异常的细胞内信号转导有助于肿瘤的发生，并可能成为新的治疗靶点。有丝分裂原/细胞外信号调节的激酶-5(MEK5)的过度表达与侵袭性前列腺癌有关。在这项研究中，我们研究了细胞外信号调节激酶(ERK5，一种MAPK和MEK5的特异性底物)在前列腺癌中的作用。与良性前列腺增生症相比，高级别前列腺癌中ERK5免疫反应显著上调(P<；0.0001)。ERK5胞浆信号增强与Gleason sum评分(P<；0.0001)、骨转移(P=0.0044)和确诊时局部晚期疾病(P=0.0023)密切相关，与疾病特异性生存期较短(P=0.036)的相关性较弱。一组患者表现出很强的核ERK5定位，这与疾病特异性生存不良相关，并且在多变量分析中是一个独立的预后因素(P<；0.0001)。对匹配的肿瘤对(激素复发前后，n=26)的分析表明，ERK5的核表达与激素不敏感疾病显著相关(P=0.0078)。类似地，ERK5蛋白在雄激素非依赖性LNCaP亚系中的表达增加。我们在体外和体内获得了以下证据来支持上述表达数据：(1)共转染ERK5wt和MEK5D结构的PC3细胞导致ERK5核定位占优势，与侵袭性临床疾病中观察到的结果相似；(2)过表达ERK5的PC3细胞在体外增强了增殖、迁移和侵袭能力(P<；0.0001)，并且显著更有效地形成肿瘤，体内肿瘤达到临界体积1000 mm(3)的平均时间更短(P<；0.0001)；(3)MEK1抑制剂PD184352在低剂量时阻断ERK1/2的激活，但在抑制ERK5激活所需的较高剂量时不抑制细胞的增殖，并显著抑制细胞的增殖。综上所述，我们的结果证实了ERK5在侵袭性前列腺癌中的潜在重要性。
Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P < 0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P < 0.0001), bony metastases (P = 0.0044) and locally advanced disease at diagnosis (P = 0.0023), with a weak association with shorter disease-specific survival (P = 0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor diseasespecific survival and, on multivariant analysis, was an independent prognostic factor (P < 0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n = 26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P = 0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P < 0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm(3), in vivo (P < 0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer.