Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF.
Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF.
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DOI：
10.1186/1476-4598-9-148
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发表时间：
2010-06-15
期刊：
影响因子：
37.3
通讯作者：
Koul HK
中科院分区：
文献类型：
--
作者：
Johnson TR;Koul S;Kumar B;Khandrika L;Venezia S;Maroni PD;Meacham RB;Koul HK
前列腺源性Ets因子（PDEF）在包括前列腺在内的高上皮含量组织中表达，尽管其确切功能尚未完全确定。传统疗法对局限性前列腺癌患者的治愈率很高，但目前还没有有效的治疗方法来干预转移性前列腺癌。这些事实强调需要开发用于侵袭性前列腺癌患者的早期诊断的新方法，以及将改善难治性前列腺癌的前景的基于机制的抗转移疗法。在这项研究中，我们评估前列腺衍生Ets因子（PDEF）在前列腺癌中的作用。我们观察到前列腺癌细胞系中PDEF表达的降低与侵袭性表型的增加相关，并且在转移性前列腺癌细胞系中PDEF蛋白完全丧失。通过免疫组织化学方法在高Gleason分级前列腺癌样品中证实了PDEF表达的缺失。PDEF的重新引入深刻地影响了细胞行为，导致在三维培养中侵袭性较小的表型。此外，表达PDEF的细胞改变了细胞形态，降低了FAK磷酸化，降低了集落形成、细胞迁移和细胞侵袭力。相比之下，PDEF敲除导致迁移和侵袭以及克隆形成活性增加。我们的研究结果还表明，PDEF下调MMP 9启动子活性，抑制MMP 9 mRNA的表达，并导致MMP 9活性在前列腺癌细胞中的损失。这些结果表明，在侵袭性前列腺癌中，PDEF的丢失可能与MMP 9表达和活性增加有关。为了证实结果，我们研究了前列腺癌临床样品中的MMP 9表达。这些研究的结果表明，MMP 9表达增加与晚期Gleason分级相关。总之，我们的研究结果表明，在向侵袭性前列腺癌转变期间，PDEF表达降低，MMP9表达增加。这些研究首次证明PDEF对MMP 9表达的负调节，并且PDEF表达在侵袭性前列腺癌中丢失，并且与前列腺癌临床样品中的MMP 9表达负相关。基于这些令人兴奋的结果，我们提出PDEF的缺失沿着MMP 9表达的增加应该作为早期检测侵袭性前列腺癌的新标志物。
Prostate-derived Ets factor (PDEF) is expressed in tissues of high epithelial content including prostate, although its precise function has not been fully established. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is, at present, no effective treatment for intervention in metastatic prostate cancer. These facts underline the need to develop new approaches for early diagnosis of aggressive prostate cancer patients, and mechanism based anti-metastasis therapies that will improve the outlook for hormone-refractory prostate cancer. In this study we evaluated role of prostate-derived Ets factor (PDEF) in prostate cancer. We observed decreased PDEF expression in prostate cancer cell lines correlated with increased aggressive phenotype, and complete loss of PDEF protein in metastatic prostate cancer cell lines. Loss of PDEF expression was confirmed in high Gleason Grade prostate cancer samples by immuno-histochemical methods. Reintroduction of PDEF profoundly affected cell behavior leading to less invasive phenotypes in three dimensional cultures. In addition, PDEF expressing cells had altered cell morphology, decreased FAK phosphorylation and decreased colony formation, cell migration, and cellular invasiveness. In contrast PDEF knockdown resulted in increased migration and invasion as well as clonogenic activity. Our results also demonstrated that PDEF downregulated MMP9 promoter activity, suppressed MMP9 mRNA expression, and resulted in loss of MMP9 activity in prostate cancer cells. These results suggested that loss of PDEF might be associated with increased MMP9 expression and activity in aggressive prostate cancer. To confirm results we investigated MMP9 expression in clinical samples of prostate cancer. Results of these studies show increased MMP9 expression correlated with advanced Gleason grade. Taken together our results demonstrate decreased PDEF expression and increased MMP9 expression during the transition to aggressive prostate cancer. These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, and that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP9 expression in clinical samples of prostate cancer. Based on these exciting results, we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer.
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