Mechanisms of Carcinoma Differentiation and Invasion

癌分化和侵袭的机制

• 批准号: 8507623
• 负责人: Arthur M Mercurio
• 金额: $ 32.46万
• 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/8507623
• 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; 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; 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）：本提案中要解决的首要问题是雌激素受体如何丧失？(ER?)肿瘤细胞的功能导致前列腺癌。ER的表达？在前列腺癌中，特别是在侵袭性、高Gleason分级肿瘤中，其减少，并且其损失有助于去分化的EMT表型。重要的是，失去？增加Bmi-1的表达，Bmi-1是一种Polycomb组转录抑制因子，作为一种癌蛋白发挥作用，并与前列腺肿瘤干细胞的自我更新有关。一个关键的问题，从这些发现是如何损失的ER？有助于Bmi-1表达和肿瘤起始细胞的推定调节。急诊室？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着升高的HIF-1？？但在包括高级别肿瘤的局部原发性前列腺癌中未观察到临床相关的缺氧。这些观察结果表明，损失的ER？前列腺癌通过稳定HIF-1？模拟缺氧。有人建议，ER？是必需的特定脯氨酰羟化酶的目标HIF-1的表达？降解，提供了一个潜在的机制，如何损失ER？诱导HIF-1？，并且该机制的主要结果是增强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的和令人兴奋的假设，ER？阻碍了EMT过程的获得，EMT过程扩大了肿瘤起始细胞的群体并增强了它们的自我更新，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，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？促进HIF-1蛋白体的降解。通过维持脯氨酰羟化酶2（PHD 2）的转录，以及ER的丢失？表达或功能减少PHD 2的表达，导致HIF-1？稳定和HIF-1激活，促进去分化的EMT表型。第二个目标是建立ER？信号传导抑制HIF-1介导的VEGF转录，其以自分泌方式发挥作用以维持Bmi-1的表达，促进EMT并有助于前列腺肿瘤起始细胞的功能。“那是因为，他的损失。和PHD 2通过促进EMT和增加肿瘤起始细胞的频率而促成肿瘤发生和侵袭性疾病。