Mechanisms of Carcinoma Differentiation and Invasion

描述(由申请人提供)：这项提案中要解决的首要问题是雌激素受体如何丢失？(呃？)肿瘤细胞的功能与前列腺癌有关。ER？在前列腺癌中，尤其是在侵袭性的、高Gleason分级的肿瘤中，它的缺失会导致去分化的EMT表型。重要的是，急诊室的损失？增加BMI-1的表达，BMI-1是一种多梳族转录抑制因子，作为一种癌蛋白发挥作用，并与前列腺癌干细胞的自我更新有关。从这些发现中产生的一个关键问题是内质网如何丢失？有助于BMI-1的表达和对肿瘤启动细胞的可能调节。呃？稳定HIF-1并促进HIF-1介导的转录，但参与这一关键过程的机制尚未解决。这一机制是非常重要和相关的，因为高级别肿瘤表现出HIF-1的显着升高，但在包括高级别肿瘤在内的局限性原发性前列腺癌中，临床上未见相关的缺氧。这些观察表明内质网的丢失？在前列腺癌中，通过稳定HIF-1来模拟缺氧。提出ER？是特定的针对HIF-1的羟化酶表达所必需的，为内质网的丢失提供了一个潜在的机制。诱导HIF-1，这一机制的一个主要结果是增强了血管内皮生长因子的转录和血管内皮生长因子介导的诱导BMI-1。总而言之，这一应用程序将解决新的和令人兴奋的假设，即ER？阻碍EMT过程的获得，该过程扩大肿瘤起始细胞的数量并增强其自我更新，并且前列腺癌的进展可以通过维持ER？功能。为了验证这一假设，本文提出了两个具体目标。第一个目的将确定配体依赖的ER？激活。通过维持Prolyl羟基酶2(PHD2)的转录，促进HIF-1蛋白酶体的降解，而ER？表达或功能减少PHD2的表达，导致HIF-1？？稳定和HIF-1激活，从而促进去分化的EMT表型。第二个目标是建立ER？信号转导抑制HIF-1介导的血管内皮细胞生长因子的转录，血管内皮生长因子以自分泌的方式维持BMI-1的表达，促进EMT，并有助于前列腺癌的启动细胞的功能。由此，就可以确定ER的损失？和PHD2通过促进EMT和增加肿瘤起始细胞的频率而促进肿瘤的发生和侵袭性疾病。

DESCRIPTION (provided by applicant): The overarching question to be addressed in this proposal is how loss of estrogen receptor ? (ER?) function in tumor cells contributes to prostate cancer. The expression of ER? is diminished in prostate cancer, especially in aggressive, high Gleason grade tumors and its loss contributes to a de-differentiated, EMT phenotype. Importantly, loss of ER? increases expression of Bmi-1, a Polycomb group transcriptional repressor that functions as an oncoprotein and has been implicated in the self-renewal of prostate tumor stem cells. A key issue that arises from these findings is how loss of ER? contributes to Bmi-1 expression and the putative regulation of tumor initiating cells. ER? stabilizes HIF-1??and promotes HIF-1-mediated transcription but the mechanism involved in this critical process has not been resolved. This mechanism is extremely important and relevant because high-grade tumors exhibit significantly elevated expression of HIF-1??but clinically relevant hypoxia is not seen in localized primary prostate cancer including high-grade tumors. These observations indicate that loss of ER? in prostate cancer mimics hypoxia by stabilizing HIF-1?. It is proposed that ER? is necessary for the expression of specific prolyl hydroxylases that target HIF-1??for degradation, providing a potential mechanism for how loss of ER? induces HIF-1?, and that a major consequence of this mechanism is enhanced VEGF transcription and VEGF-mediated induction of Bmi-1. Collectively, this application will address the novel and exciting hypothesis that ER? impedes the acquisition of an EMT process that expands the population of tumor initiating cells and enhances their self-renewal, and that the progression of prostate cancer can be diminished by sustaining ER? function. To validate this hypothesis, two specific aims are proposed. The first aim will determine that ligand-dependent activation of ER? promotes the proteosomal degradation of HIF-1??by sustaining the transcription of prolyl hydroxylase 2 (PHD2), and that loss of ER? expression or function diminishes PHD2 expression resulting in HIF-1??stabilization and HIF-1 activation that promotes a de-differentiated, EMT phenotype. The second aim will establish that ER? signaling suppresses the HIF-1-mediated transcription of VEGF, which functions in an autocrine manner to sustain the expression of Bmi-1, promote an EMT and contribute to the function of prostate tumor initiating cells. Thus, it will be determined that loss of ER? and PHD2 contribute to tumorigenesis and aggressive disease by promoting an EMT and increasing the frequency of tumor initiating cells.