Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion
Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion
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DOI：
10.1002/ijc.25005
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发表时间：
2010-07-01
影响因子：
6.4
通讯作者：
Cheung, Annie N. Y.
中科院分区：
文献类型：
--
作者：
Siu, Michelle K. Y.;Wong, Esther S. Y.;Cheung, Annie N. Y.
卵巢癌是一种死亡率较高的妇科恶性肿瘤。因此，确定新的预后和治疗靶点是重要的。P21激活的蛋白激酶(PAK)参与了细胞酮的重组。本研究探讨卵巢癌中总的和磷酸化的(P)Pala和Pak2的临床意义及其功能作用。应用免疫组织化学方法检测了Ak1、p-Pak1、Thr(212)、Pak2和p-Pak2Ser(20)在正常卵巢细胞系、卵巢癌细胞系和卵巢肿瘤临床标本中的表达。检测Pak1和Pak2对卵巢癌细胞功能的影响。PAK1、p-pak1和p-pak2在卵巢癌细胞系中均有过表达，并与卵巢良性病变/包涵体囊肿进行了比较。在正常细胞系、癌变细胞系和临床标本中也观察到类似的pak2表达水平。经多项检验校正后，卵巢癌组织中Pak1的高表达和核p-Pak1的表达分别与组织学类型和肿瘤分级显著相关。PAK1和p-pak1的表达与总体生存率和无病生存期相关。PAK1是一个独立的预后因素。在卵巢癌细胞系中，Pak1和Pak2基因的敲除减少了细胞的迁移和侵袭，但不影响细胞的增殖和凋亡。Pak1基因的敲除也降低了p38的激活，下调了血管内皮生长因子的表达。相反，异位pak1的过表达以一种依赖于激酶的方式促进了卵巢癌细胞的迁移和侵袭，同时增加了p38的激活。我们的研究结果表明，Pak1、p-Pak1和p-Pak2在卵巢癌的发生发展中起重要作用。PAK1和p-pak1可能是卵巢癌潜在的预后标志物和治疗分子靶点。
Ovarian cancer is a gynecological malignancy with high mortality. Therefore, the identification of novel prognostic and therapeutic targets is important. p21-activated kinases (Paks) are involved in cytosketeton reorganization. This study investigated the clinical significance of total and phosphorylated (p) Pala and Pak2 as well as their functional roles in ovarian cancer. Expressions of Pak1, p-Pak1 Thr(212), Pak2 and p-Pak2 Ser(20) in ovarian normal and cancerous cell lines as well as in clinical samples of ovarian tumors were evaluated. The effects of Pak1 and Pak2 on ovarian cancer cell functions were determined. Pak1, p-Pak1 and p-Pak2 were overexpressed in ovarian cancer cell lines, and clinical samples of ovarian cancers were compared with benign ovarian lesions/inclusion cysts. Similar Pak2 expression levels were observed among normal and cancerous cell tines and clinical samples. After multiple testing correction, high Pak1 and nuclear p-Pak1 expression in ovarian cancers was significantly associated with histological type and tumor grade, respectively. Pak1 and p-Pak1 expression was associated with poor overall and disease-free survival. Pak1 was an independent prognostic factor. Knockdown of Pak1 and Pak2 in ovarian cancer cell lines reduced cell migration and invasion but did not affect cell proliferation and apoptosis. Knockdown of Pak1 also reduced p38 activation and downregulated vascular endothelial growth factor. Conversely, ectopic Pak1 overexpression enhanced ovarian cancer cell migration and invasion in a kinase-dependent manner, along with increased p38 activation. Our findings suggest that Pak1, p-Pak1 and p-Pak2 play important roles in ovarian carcinogenesis. Pak1 and p-Pak1 may be potential prognostic markers and therapeutic molecular targets in ovarian cancer.