Mechanisms of Carcinoma Differentiation and Invasion

描述（由申请人提供）：本提案中要解决的首要问题是雌激素受体如何丢失？（ER?）功能导致前列腺癌。ER？在前列腺癌中，特别是在侵袭性的高格里森级肿瘤中，它的减少导致了去分化的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Polycomb组转录抑制因子，具有癌蛋白的功能，与前列腺肿瘤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ER的损失是如何产生的？有助于Bmi-1的表达和肿瘤起始细胞的可能调节。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得到解决。这一机制是非常重要和相关的，因为高级别肿瘤表现出显著升高的HIF-1表达。但临床上相关的缺氧在局限性原发性前列腺癌包括高级别肿瘤中未见。这些观察结果表明，ER？前列腺癌通过稳定HIF-1来模拟缺氧。建议ER？是表达针对HIF-1的特定脯氨酸羟化酶所必需的。为降解提供了一个潜在的机制，如何损失ER？诱发HIF-1吗?该机制的一个主要结果是增强VEGF转录和VEGF介导的Bmi-1诱导。总的来说，这个应用程序将解决新颖而令人兴奋的假设，即ER？阻碍了EMT过程的获得，该过程扩大了肿瘤启动细胞的数量并增强了它们的自我更新，并且可以通过维持ER来减少前列腺癌的进展。函数。为了验证这一假设，提出了两个具体目标。第一个目标是确定内质网的配体依赖性激活？促进HIF-1蛋白体降解？？通过维持脯氨酰羟化酶2 （PHD2）的转录，以及ER？表达或功能降低PHD2表达导致HIF-1？稳定和HIF-1激活，促进去分化，EMT表型。第二个目标是建立急诊室？信号传导抑制hif -1介导的VEGF转录，而VEGF以自分泌方式维持Bmi-1的表达，促进EMT并促进前列腺肿瘤启动细胞的功能。因此，可以确定ER的损失为？和PHD2通过促进EMT和增加肿瘤起始细胞的频率来促进肿瘤发生和侵袭性疾病。

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.