Mechanisms of Carcinoma Differentiation and Invasion

癌分化和侵袭的机制

• 批准号: 8658042
• 负责人: Arthur M Mercurio
• 金额: $ 33.68万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658042
• 关键词: Address; Autocrine Communication; Carcinoma; Cells; Characteristics; Disease; Epithelial; Epithelial Cells; Estrogen Receptors; Exhibits; Frequencies; Genetic Transcription; Gleason Grade for Prostate Cancer; Goals; Hypoxia; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Neoplasm Metastasis; Nuclear Hormone Receptors; Oncogene Proteins; Phenotype; Polycomb; Population; Process; Procollagen-Proline Dioxygenase; Proline; Property; Prostate; Prostate carcinoma; Prostatic Neoplasms; Receptor Signaling; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Stem cells; Transcription Repressor/Corepressor; Tumor Stem Cells; Vascular Endothelial Growth Factors; Work; autocrine; behavior influence; clinically relevant; interest; neoplastic cell; novel; outcome forecast; receptor expression; receptor function; response; self-renewal; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）：该提案中要解决的总体问题是雌激素受体的损失？ （ER？）肿瘤细胞的功能有助于前列腺癌。 ER的表达？前列腺癌的减少，尤其是在侵略性高gleason级肿瘤中，其损失导致了脱不同的EMT表型。重要的是，ER的损失？增加了BMI-1的表达，BMI-1是一种polycomb组转录阻遏物，可作为癌蛋白起作用，并与前列腺肿瘤干细胞的自我更新有关。这些发现引起的关键问题是ER的损失如何？有助于BMI-1表达和肿瘤引发细胞的推定调节。嗯？稳定HIF-1 ??并促进HIF-1介导的转录，但涉及此关键过程的机制尚未解决。这种机制非常重要且相关，因为高级肿瘤表现出HIF-1 ??表达的显着升高，但是在包括高级肿瘤在内的局部原发性前列腺癌中未见临床相关的缺氧。这些观察结果表明ER的丧失？在前列腺癌中，通过稳定HIF-1？模仿缺氧。有人提出了ER吗？对于靶向HIF-1的降解的特定丙酰羟基酶的表达是否必要，为ER损失提供了潜在的机制？诱导HIF-1？，并且该机制的主要结果是增强了VEGF转录和VEGF介导的BMI-1诱导。总的来说，该应用程序将解决ER的新颖而令人兴奋的假设？阻碍了EMT过程的获取，该过程扩大了肿瘤启动细胞的种群并增强其自我更新，并且可以通过维持ER来减少前列腺癌的进展？功能。为了验证这一假设，提出了两个具体目标。第一个目标将确定ER的配体依赖性激活？通过维持丙酰羟化酶2（PHD2）的转录以及ER的损失来促进HIF-1 ??的蛋白质体降解？表达或功能会减少pHD2表达，从而导致HIF-1 ??稳定化和HIF-1激活，从而促进了脱节的EMT表型。第二个目标将确定ER？信号传导抑制了HIF-1介导的VEGF的转录，该转录以自分泌方式起作用以维持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，将确定ER的损失？ PHD2和PHD2通过促进EMT并增加肿瘤启动细胞的频率来促进肿瘤发生和攻击性疾病。