ERK5 signalling in prostate cancer promotes an invasive phenotype.
ERK5 signalling in prostate cancer promotes an invasive phenotype.
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DOI：
10.1038/sj.bjc.6606062
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发表时间：
2011-02-15
影响因子：
8.8
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中科院分区：
文献类型：
--
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异常的有丝分裂原/细胞外信号调节激酶5（MEK 5）-细胞外信号调节蛋白激酶5（ERK 5）-介导的信号传导已经涉及许多肿瘤类型，包括前列腺癌（PCa）。ERK 5驱动的致癌作用的分子基础及其临床意义仍有待充分表征。分别使用siRNA介导的敲低或MEK抑制剂PD 18435进行人PCa PC 3和PC 3-ERK 5（用ERK 5稳定转染）细胞中ERK 5表达或功能的调节。通过增殖、运动、侵袭和侵袭伪足的测定来评估ERK 5信号传导的体外意义。通过Q-RT-PCR测定基质金属蛋白酶/金属蛋白酶组织抑制剂的表达。采用免疫组化法检测原发性和转移性PCa中细胞外信号调节蛋白激酶5的表达。ERK 5表达或信号传导的减少显著抑制了PC 3细胞的运动和侵袭能力。在原位PCa模型中，细胞外信号调节蛋白激酶5介导的信号传导显著促进体内转移的形成（P<0.05）。在PC 3细胞中，强迫ERK 5表达也增强了侵袭伪足的形成。此外，与良性前列腺增生和原发性PCa相比，转移性PCa中细胞核ERK 5免疫反应性显著上调（分别为P=0.013和P<0.0001）。我们的体外、体内和临床数据支持MEK 5-ERK 5信号通路在侵袭性PCa中的重要作用，其代表了原发性和转移性PCa治疗的潜在靶点。
Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised. Modulation of ERK5 expression or function in human PCa PC3 and PC3–ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT–PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry. Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively). Our in vitro, in vivo and clinical data support an important role for the MEK5–ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.
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