Developmental Transcription Factors in Prostate Cancer

前列腺癌的发育转录因子

• 批准号: 7015562
• 负责人: CARLOS Sanchez MORENO
• 金额: $ 25.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-10 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015562
• 关键词: RNA interference; SCID mouse; androgens; apoptosis; carcinogenesis; cell growth regulation; cell proliferation; chromatin immunoprecipitation; clinical research; gene expression; gene expression profiling; genetically modified animals; hormone related neoplasm /cancer; human tissue; laboratory mouse; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplastic cell; neoplastic process; prognosis; prostate neoplasms; small interfering RNA; transcription factor; western blottings

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common cancer in American men and the second highest cause of cancer related death in Western males with 189,000 new cases and over 30,000 deaths annually. HOXC6 and SOX4 are hormonally regulated developmental transcription factors that may confer a stem-cell like, androgen independent phenotype to prostate cancer cells. Our global gene expression profiling of prostate cancer patients has determined that HOXC6 and SOX4 are significantly upregulated in PCa and that their expression patterns are strongly correlated with the Gleason Score (or tumor grade). Immunohistochemistry shows that SOX4 protein is increased in prostate cancer cells, and immunoblots show increased HOXC6 protein levels in prostate cancer cells. Loss of HOXC6 and SOX4 expression induces apoptosis in prostate cancer cells, while overexpression induces increased proliferation and decreased apoptosis. Potential targets of HOXC6 and SOX4 may have roles in mitogenic signaling and cell cycle regulation. However, the biological effects of altered HOXC6 and SOX4 expression in prostate cells are not well understood. In this application, we propose to test the hypothesis that HOXC6 and/or SOX4 could be novel therapeutic targets for prostate cancer. Toward this goal, we will perturb HOXC6 and SOX4 expression in prostate cancer cells and measure apoptosis, proliferation rate, androgen-dependence, and growth in soft agar. We will also analyze the effects of in vivo siRNA treatment by co-injection of human prostate cancer cells and siRNAs into nude mice. We will further examine the effect of genetic loss of HOXC6 on prostate cancer incidence and progression using HOXC6-targeted null mice as a model system. In addition, candidate sets of HOXC6- and SOX4-regulated target genes that were identified in PCa patient tissue samples will be confirmed in prostate cells by expression profiling, quantitative real-time PCR, immunoblot, and chromatin immunoprecipitation (ChIP) assays. Finally, we will determine whether SOX4 levels are predictive of patient outcome using tissue arrays. Together these experiments will provide new insights into the mechanisms of prostate cancer progression and potentially validate HOXC6 and SOX4 as novel therapeutic targets for prostate cancer.

描述（由申请人提供）：前列腺癌（PCA）是美国男性最常见的癌症，是西方男性与癌症相关的第二高原因，每年有189,000例新病例，每年超过30,000例死亡。 HOXC6和SOX4是荷尔蒙调节的发育转录因子，可能会将类似于雄激素独立表型的干细胞传达给前列腺癌细胞。我们对前列腺癌患者的全球基因表达分析已确定HOXC6和SOX4在PCA中显着上调，并且其表达模式与Gleason评分（或肿瘤等级）密切相关。免疫组织化学表明，前列腺癌细胞中SOX4蛋白的增加，免疫印迹显示前列腺癌细胞中HOXC6蛋白水平升高。 HOXC6和SOX4表达的丧失会诱导前列腺癌细胞的凋亡，而过表达会诱导增殖增加和凋亡减少。 HOXC6和SOX4的潜在靶标在有丝分裂信号传导和细胞周期调节中可能具有作用。然而，尚不清楚前列腺细胞中HOXC6和SOX4表达改变的生物学作用。在此应用中，我们建议检验以下假设：Hoxc6和/或Sox4可能是前列腺癌的新型治疗靶标。为了实现这一目标，我们将在前列腺癌细胞中扰动Hoxc6和Sox4的表达，并测量软琼脂中的凋亡，增殖率，雄激素依赖性以及生长。我们还将通过共同注射人类前列腺癌细胞和siRNA中的体内siRNA处理的影响。我们将进一步研究HOXC6遗传丧失对前列腺癌发病率和使用HOXC6靶向的无效小鼠作为模型系统的影响。此外，将通过表达分析，定量实时PCR，免疫印迹和染色质免疫沉淀（CHIP）分析来确认在PCA患者组织样品中鉴定出的HOXC6和SOX4调节的靶基因的候选候选靶基因。最后，我们将确定Sox4水平是否可以使用组织阵列预测患者的结果。这些实验将共同提供有关前列腺癌进展机制的新见解，并可能验证Hoxc6和Sox4作为前列腺癌的新型治疗靶标。