PDEF and survivin: cancer prognosis, initiation, progression and metastasis

我们的数据表明，人前列腺源性Ets转录因子（PDEF）通过下调抗凋亡蛋白survivin的表达在肿瘤抑制中发挥重要作用。PDEF阴性乳腺癌细胞中PDEF的异位表达抑制survivin的表达及其启动子活性。相比之下，PDEF阳性乳腺癌细胞中PDEF的下调在体外可上调survivin的表达，同时增加细胞增殖，在体内可增加异种移植瘤的取瘤率和肿瘤生长。重要的是，与survivin+/PDEF-肿瘤患者相比，survivin-/PDEF+肿瘤患者的生存率更高，复发率更低。细胞凋亡的异常抑制是肿瘤发生和恶性进展的关键步骤之一。尽管潜在的机制尚不完全清楚，但有证据表明，survivin在癌症的发生、进展、转移和复发中起着重要作用。因此，许多具有癌症预防和治疗作用的天然膳食成分，包括白藜芦醇、水飞蓟宾、磺胺酸、类维生素a、硒和维生素D化合物，下调了survivin的表达。PDEF似乎与survivin有相反的作用，可能是通过下调survivin的表达。研究表明PDEF可以抑制癌细胞的迁移、侵袭和生长。基于这些观察结果，我们假设使用survivin和PDEF作为相互关联的生物标志物和靶点来对survivin+/PDEF-肿瘤患者和survivin-/PDEF+肿瘤患者进行分层可能有助于前列腺癌的预后和个性化治疗。为了验证这一假设，我们提出了两个特定的目的：1)通过前列腺癌组织检测survivin和PDEF的表达状况及其与患者生存、癌症转移和肿瘤复发的关系；2)检测前列腺癌组织中PDEF基因的甲基化状态及其与PDEF和survivin表达的关系。这些研究将survivin和PDEF作为相互关联的生物标志物和靶点，可能为癌症预后和个性化医疗提供新的方法。

Our data indicate that the human prostate-derived Ets transcription factor (PDEF) plays an essential role in tumor suppression via downregulation of the expression of antiapoptotic protein survivin. Ectopic expression of PDEF in PDEF-negative breast cancer cells inhibits survivin expression as well as its promoter activity. In contrast, knockdown of PDEF in PDEF-positive breast cancer cells upregulates survivin expression along with increased cell proliferation in vitro, and increases xenograft tumor take rate and tumor growth in vivo. Importantly, patients with survivin-/PDEF+ tumor show better survival and less relapse than patients with survivin+/PDEF- tumor. Abnormal inhibition of apoptosis is known to be one of the critical steps for oncogenesis and malignant progression. Although the underlying mechanisms are not fully understood, evidence indicates that survivin plays an important role in the initiation, progression, metastasis and recurrence of cancer. Accordingly, many natural dietary components, including resveratrol, silibinin, sulindac, retinoid, selenium and vitamin D compounds that have cancer-preventive and therapeutic effects, downregulate survivin expression. PDEF appears to have an opposing role to survivin and likely via downregulation of survivin expression. It has been shown that PDEF inhibits cancer cell migration, invasion and growth. Based on these observations, we hypothesize that application of survivin and PDEF as interconnected biomarkers and targets to stratify patents with survivin+/PDEF- tumor and patients with survivin-/PDEF+ tumor may facilitate prostate cancer prognosis and personalized medicine. Two specific aims are proposed to test this hypothesis: 1) determine survivin and PDEF expression status and their association with patient survival, cancer metastasis and tumor relapse using prostate cancer tissues; and 2) determine methylation status of the PDEF gene in prostate cancer tissues and its association with the expression of PDEF and survivin. These studies may provide novel approaches for cancer prognosis and personalized medicine, by considering survivin and PDEF as interconnected biomarkers and targets.