Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Denver Veterans Administrative Medical Center, and University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.
Mol Cancer. 2010 Jun 15;9:148. doi: 10.1186/1476-4598-9-148.
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.
前列腺衍生的 Ets 因子（PDEF）在高上皮含量的组织中表达，包括前列腺，尽管其确切功能尚未完全确定。传统疗法为局部前列腺癌患者提供了很高的治愈率，但目前尚无有效的干预转移性前列腺癌的治疗方法。这些事实强调了需要开发新的方法来早期诊断侵袭性前列腺癌患者，并开发基于机制的抗转移疗法，以改善激素难治性前列腺癌的预后。在这项研究中，我们评估了前列腺衍生的 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 表达降低与侵袭表型增加相关，并且在转移性前列腺癌细胞系中完全丧失了 PDEF 蛋白。免疫组织化学方法证实高格里森分级前列腺癌样本中 PDEF 表达缺失。PDEF 的重新引入对细胞行为产生了深远的影响，导致三维培养中侵袭性表型减少。此外，PDEF 表达细胞的细胞形态发生改变，FAK 磷酸化减少，集落形成、细胞迁移和细胞侵袭减少。相比之下，PDEF 敲低导致迁移和侵袭增加以及集落形成活性增加。我们的结果还表明，PDEF 下调 MMP9 启动子活性，抑制 MMP9 mRNA 表达，并导致前列腺癌细胞中 MMP9 活性丧失。这些结果表明，PDEF 的丢失可能与侵袭性前列腺癌中 MMP9 的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本中的 MMP9 表达。这些研究的结果表明，MMP9 表达增加与高级格里森分级相关。综上所述，我们的研究结果表明，在向侵袭性前列腺癌转变过程中，PDEF 表达降低和 MMP9 表达增加。
这些研究首次证明了 PDEF 对 MMP9 表达的负调控作用，并且在侵袭性前列腺癌中 PDEF 表达缺失，并且与前列腺癌临床样本中的 MMP9 表达呈负相关。基于这些令人兴奋的结果，我们提出 PDEF 缺失和 MMP9 表达增加应作为早期检测侵袭性前列腺癌的新标志物。
