Function of the Stem Cell Transcription Factor Sox2 in Prostate Cancer

干细胞转录因子 Sox2 在前列腺癌中的功能

基本信息

批准号：
9228342
负责人：
Donald James Vander Griend
金额：
$ 32.32万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228342
关键词：
Adult American Androgen Antagonists Androgen Receptor Androgens Basal Cell Binding Biological Markers Cancer Etiology Castration Cell Death Cell Proliferation Cell Survival Cells ChIP-seq Clinical Data Developmental Gene Disease Environment Epigenetic Process Epithelial Cells FGF5 gene Gene Chips Gene Expression Gene Targeting Genes Genetic Transcription Goals Growth Indolent Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediator of activation protein Metastatic to Neoplasm Metastasis Oncogenes Patients Prostate Prostatic Neoplasms Receptor Signaling Relapse Resistance Role Seminal Vesicles Signal Pathway Stem cells Tissues Tumor-Derived Tumorigenicity Undifferentiated Work androgen deprivation therapy cancer cell cancer initiation castration resistant prostate cancer cell growth embryonic stem cell gene function human embryonic stem cell human tissue improved in vivo knock-down men mortality novel pluripotency prostate cancer cell public health relevance sex targeted treatment taxane transcription factor tumor tumor initiation tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer related mortalities among American men. For advanced prostate cancers, androgen deprivation therapy (ADT) has been the mainstay treatment for nearly 70 years. Malignant relapse of prostate cancer after ADT (commonly referred to as castration-resistant prostate cancer, or CRPC), however, is a significant clinical problem and new strategies are needed to improve patient survival. In contrast to the prostate, cancers arising in the seminal vesicle are exceedingly rare. To identify new genes and signaling pathways involved in prostate cancer initiation and progression we conducted an expression array analyses comparing normal prostate vs. seminal vesicle epithelial cells and identified Sox2 [SRY (sex determining region Y)- box 2] as one of many developmental genes that are highly expressed in adult prostate epithelial cells. Sox2 is an essential transcription factor for maintaining the survival and pluripotency of undifferentiated embryonic stem cells (ESCs), and has an emerging role as an epigenetic reprogramming factor and oncogene. The function of Sox2 in embryonic stem cells is well defined and requires other essential co-factors such as Oct4 and Nanog. In adult prostate tissues and tumors, however, such Sox2 transcriptional co-factors are not expressed, suggesting that Sox2 has unique, non-stem cell gene targets and functions within adult cells. Little is known, however, about the function and clinical impact of Sox2 expression in prostate cancer, and the relationship between Sox2 and the Androgen Receptor (AR) in metastatic, castration-resistant prostate cancer. The long term goal of this project is to elucidate the signaling pathways regulated by Sox2 which can be used to predict cancer progression and can be targeted for the treatment of advanced prostate cancers. The objective of this proposal is to define the mechanism of how Sox2 promotes cell survival and growth in an androgen-deprived environment. Our central hypothesis is that Sox2 functions as an oncogene by regulating a novel set of gene targets to promote cancer cell survival and proliferation, and not via mechanisms of inhibiting differentiation and promoting pluripotency. This mechanism of Sox2 function occurs via interaction with transcriptional co-regulators unique to adult epithelial cells, and not Oct4 or Nanog.

描述（由申请人提供）：前列腺癌是最常见的非皮肤癌，也是美国男性癌症相关死亡的第二大原因。对于晚期前列腺癌，雄激素剥夺疗法 (ADT) 近 70 年来一直是主要治疗方法。然而，ADT 后前列腺癌的恶性复发（通常称为去势抵抗性前列腺癌或 CRPC）是一个重大的临床问题，需要新的策略来提高患者的生存率。与前列腺相反，精囊中发生的癌症极其罕见。为了确定参与前列腺癌发生和进展的新基因和信号通路，我们进行了表达阵列分析，比较了正常前列腺与精囊上皮细胞，并确定了 Sox2 [SRY（性别决定区 Y）- 框 2] 作为许多发育基因之一在成人前列腺上皮细胞中高度表达。 Sox2 是维持未分化胚胎干细胞 (ESC) 存活和多能性的重要转录因子，并且作为表观遗传重编程因子和癌基因发挥着新兴作用。 Sox2 在胚胎干细胞中的功能已明确，并且需要其他重要的辅助因子，例如 Oct4 和 Nanog。然而，在成人前列腺组织和肿瘤中，此类 Sox2 转录辅助因子并不表达，这表明 Sox2 在成人细胞内具有独特的非干细胞基因靶标和功能。然而，人们对 Sox2 表达在前列腺癌中的功能和临床影响以及转移性去势抵抗性前列腺癌中 Sox2 与雄激素受体 (AR) 之间的关系知之甚少。该项目的长期目标是阐明Sox2调节的信号通路，可用于预测癌症进展，并可靶向治疗晚期前列腺癌。该提案的目的是确定 Sox2 如何在雄激素剥夺的环境中促进细胞存活和生长的机制。我们的中心假设是，Sox2 作为癌基因发挥作用，通过调节一组新的基因靶标来促进癌细胞存活和增殖，而不是通过抑制分化和促进多能性的机制。 Sox2 功能的这种机制是通过与成体上皮细胞特有的转录共调节因子相互作用而发生的，而不是与 Oct4 或 Nanog 相互作用。