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的表达而在肿瘤抑制中发挥重要作用。PDEF在PDEF阴性乳腺癌细胞中的异位表达抑制Survivin的表达及其启动子活性。相反，在PDEF阳性的乳腺癌细胞中，PDEF基因的敲除上调了Survivin的表达，并在体外增加了细胞的增殖，增加了异种移植瘤的成瘤率和体内肿瘤的生长。重要的是，Survivin-/PDEF+肿瘤患者比Survivin+/PDEF-肿瘤患者有更好的生存率和更少的复发。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。尽管其潜在的机制尚不完全清楚，但有证据表明，Survivin在肿瘤的发生、发展、转移和复发中起着重要作用。因此，许多天然饮食成分，包括白藜芦醇、水飞蓟宾、舒林酸、维甲酸、硒和维生素D化合物，具有预防和治疗癌症的作用，下调Survivin的表达。PDEF似乎与Survivin具有相反的作用，可能是通过下调Survivin的表达来实现的。研究表明，PDEF可抑制癌细胞的迁移、侵袭和生长。基于这些观察，我们推测，应用Survivin和PDEF作为相互关联的生物标志物和靶点，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用药。为了验证这一假设，人们提出了两个特定的目标：1)利用前列腺癌组织确定Survivin和PDEF的表达状态及其与患者生存、肿瘤转移和肿瘤复发的关系；2)确定前列腺癌组织中PDEF基因的甲基化状态及其与PDEF和Survivin表达的关系。这些研究可能通过将Survivin和PDEF作为相互关联的生物标记物和靶点，为癌症预后和个性化药物治疗提供新的方法。

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.