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

PDEF 和生存素：癌症预后、起始、进展和转移

• 批准号: 7871433
• 负责人: Fengzhi Li
• 金额: $ 33.9万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871433
• 关键词: Abbreviations; Adenocarcinoma; Adult; Animal Model; Animals; Biological Markers; Breast Cancer Cell; Cancer Prognosis; Cell Proliferation; Colorectal; Data; Diagnostic Neoplasm Staging; Dietary Component; Down-Regulation; Drug toxicity; Ectopic Expression; Growth; Human; In Vitro; Inhibition of Apoptosis; Island; Knowledge; Legal patent; Life; Luciferases; MCF7 cell; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medicine; Methylation; Mitotic; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; Patients; Pharmaceutical Preparations; Play; Preventive; Prognostic Marker; Prostate; Prostatic Neoplasms; Proteins; Recurrence; Recurrent disease; Relapse; Research Design; Resveratrol; Retinoids; Role; Screening procedure; Selenium; Sulindac; Testing; Therapeutic Effect; Time; Tissues; Transcription factor genes; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Virus; Vitamin D; base; cancer cell; cancer initiation; cancer recurrence; carcinogenesis; cell motility; clinical application; in vivo; inhibitor/antagonist; mouse model; novel; novel strategies; ovarian neoplasm; promoter; radiation resistance; response; silibinin; survivin; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; tumor xenograft; tumorigenesis

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.

我们的数据表明，人前列腺衍生的Ets转录因子（PDEF）通过下调抗凋亡蛋白生存素的表达在肿瘤抑制中起着至关重要的作用。PDEF阴性乳腺癌细胞中PDEF的异位表达抑制了生存素的表达及其启动子活性。相反，PDEF阳性乳腺癌细胞中PDEF的敲低上调存活素表达沿着体外细胞增殖的增加，并增加体内异种移植肿瘤发生率和肿瘤生长。重要的是，存活素-/PDEF+肿瘤患者比存活素+/PDEF-肿瘤患者显示出更好的存活率和更少的复发。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未完全清楚，但有证据表明生存素在癌症的发生、发展、转移和复发中起重要作用。因此，许多具有癌症预防和治疗作用的天然膳食组分，包括白藜芦醇、水飞蓟宾、舒林酸、类维生素A、硒和维生素D化合物，下调存活素表达。PDEF似乎具有与存活素相反的作用，并且可能通过下调存活素表达。研究表明，PDEF可抑制癌细胞迁移、侵袭和生长。基于这些观察结果，我们假设，应用生存素和PDEF作为相互关联的生物标志物和靶点，对生存素+/PDEF-肿瘤患者和生存素-/PDEF+肿瘤患者进行分层，可能有助于前列腺癌预后和个性化治疗。提出了两个具体目的来检验该假设：1）使用前列腺癌组织确定存活素和PDEF表达状态及其与患者存活、癌症转移和肿瘤复发的关联;和2）确定前列腺癌组织中PDEF基因的甲基化状态及其与PDEF和存活素表达的关联。这些研究可能为癌症预后和个性化医疗提供新的方法，通过考虑生存素和PDEF作为相互关联的生物标志物和靶标。

项目成果

Genome-wide methylation patterns provide insight into differences in breast tumor biology between American women of African and European ancestry.

• DOI: 10.18632/oncotarget.1599
• 发表时间: 2014-01-15
• 期刊: Oncotarget
• 作者: Ambrosone CB;Young AC;Sucheston LE;Wang D;Yan L;Liu S;Tang L;Hu Q;Freudenheim JL;Shields PG;Morrison CD;Demissie K;Higgins MJ
• 通讯作者: Higgins MJ