Function of the Stem Cell Transcription Factor Sox2 in Prostate Cancer

描述（由申请人提供）：前列腺癌是最常见的非皮肤癌症，也是美国男性癌症相关死亡的第二大原因。近70年来，雄激素剥夺疗法（ADT）一直是晚期前列腺癌的主要治疗方法。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，CRPC）是一个重要的临床问题，需要新的策略来提高患者的生存率。与前列腺癌相比，精囊癌是非常罕见的。为了确定参与前列腺癌发生和发展的新基因和信号通路，我们对正常前列腺细胞和精囊上皮细胞进行了表达阵列分析，并发现Sox2 [SRY（性别决定区Y）- box 2]是成人前列腺上皮细胞中高表达的众多发育基因之一。Sox2是维持未分化胚胎干细胞（ESCs）存活和多能性的重要转录因子，并作为表观遗传重编程因子和癌基因发挥着新的作用。Sox2在胚胎干细胞中的功能是明确的，需要其他必要的辅助因子，如Oct4和Nanog。然而，在成人前列腺组织和肿瘤中，Sox2转录辅助因子不表达，这表明Sox2在成人细胞中具有独特的非干细胞基因靶点和功能。然而，对于Sox2在前列腺癌中表达的功能和临床影响，以及Sox2与雄激素受体（AR）在转移性去势抵抗性前列腺癌中的关系，我们知之甚少。该项目的长期目标是阐明Sox2调控的信号通路，可用于预测癌症进展，并可靶向治疗晚期前列腺癌。本提案的目的是确定Sox2如何在雄激素缺乏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作为癌基因通过调节一组新的基因靶点来促进癌细胞的存活和增殖，而不是通过抑制分化和促进多能性的机制。Sox2的这种功能机制是通过与成人上皮细胞特有的转录共调节因子相互作用发生的，而不是与Oct4或Nanog相互作用。

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.