Steroid receptor coactivator-3 and cancer stem cells

类固醇受体辅激活因子3和癌症干细胞

• 批准号: 8757078
• 负责人: Ray-Chang Wu
• 金额: $ 20.68万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757078
• 关键词: Cancer Patient; Cancer Relapse; Cell physiology; Colorectal Cancer; Development; Diagnostic Neoplasm Staging; Dimensions; Disease; Disease-Free Survival; Goals; Health; Human; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; MicroRNAs; Mission; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Patients; Phosphorylation; Quality of life; Regulation; Reporting; Research; Resistance; Role; Signal Transduction; Somatic Cell; Staging; Steroid Receptors; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; Tumor stage; cancer cell; cancer stem cell; cancer therapy; driving force; embryonic stem cell; improved; innovation; insight; malignant breast neoplasm; novel; overexpression; programs; public health relevance; self-renewal; stem cell therapy; therapy resistant; treatment response; tumor; tumor progression

DESCRIPTION (provided by applicant): Steroid receptor coactivator-3 (SRC-3) is the second most overexpressed oncogenes and high SRC-3 expression correlates well with resistance to therapy and reduces disease free survival. In contrast, expression of tumor suppressor miR-34a is suppressed in cancer stem cells (CSCs), and re-expression of miR-34a inhibits CSCs function. Elucidating how expression of miR-34a is suppressed in CSCs is clearly important. In this application, we focus on the regulation of miR-34a by SRC-3 and its role in cancer progression. Interestingly, SRC-3 functions as a 'corepressor' and not a 'coactivator' to suppress miR-34a expression. Expression of SRC-3 is positively correlated with tumor grades and stages, but inversely correlated with expression of miR-34a in breast cancer, suggesting a causal relationship between SRC-3 and miR-34a expression and the disease state of breast cancer. This is the first report of a 'corepressor' function of SRC-3, the significance and the mechanism whereby SRC-3 functions as a 'corepressor' to suppress expression of miR-34a remains to be identified. Our central hypothesis is that SRC-3 functions as a 'corepressor' in a context- and signaling-dependent manner to suppress miR-34a expression and promote CSCs activity. The objective of this application is to identify the mechanism which dictates the 'corepressor' function of SRC-3, and to demonstrate the role of SRC-3-miR-34a pathway in CSCs. We will achieve our objective by pursuing two aims. Aim 1. Identify a 'corepressor' activity from oncogenic coactivator SRC-3. Despite its importance as a tumor suppressor, how expression of miR-34a is suppressed in CSCs is not known. To understand how miR-34a is suppressed by SRC-3, transcription repressor regulatory factor X1 (RFX1) and de- phosphorylation of SRC-3 at S505 were identified as potential determinants for the 'corepressor' function of SRC-3. This is the first report of a 'corepressor' activity from an oncogenic 'coactivator' SRC-3, our objective is to elucidate the mechanism by which de-phosphorylation of SRC-3 at S505 dictates its 'corepressor' function with RFX1 to suppress miR-34a expression. Aim 2. Define the function of SRC-3 'corepressor' activity. MiR-34a is an important tumor suppressor that inhibits CSCs function. SRC-3 and RFX1 are identified to be novel suppressors of miR-34a expression. Our objective of this aim is to demonstrate that the 'corepressor' activity of SRC-3 with RFX1 promotes CSCs function by suppressing miR-34a expression. Our study is highly innovative and significant. It demonstrates that SRC-3 functions as a 'corepressor' in the CSCs-enriched niche to promote CSCs function by suppressing miR-34a. It is the first to reveal the 'corepressor' function of SRC-3 depends on transcriptional repressor RFX1 and its own de-phosphorylation. Our study uncovers a novel 'corepressor' activity that governs the function of SRC-3 in CSCs. This is a significant step toward our long-term goal of identifying a targetable SRC-3 CSCs pathway that will be instrumental for development of anti-CSCs therapy to improve treatment response and survival of cancer patients.

描述（由申请人提供）：类固醇受体辅激活因子 3 (SRC-3) 是第二大过度表达的癌基因，高 SRC-3 表达与治疗耐药性密切相关，并降低无病生存率。相反，肿瘤抑制因子 miR-34a 的表达在癌症干细胞 (CSC) 中受到抑制，并且 miR-34a 的重新表达会抑制 CSC 的功能。阐明 CSC 中 miR-34a 的表达如何受到抑制显然很重要。在此应用中，我们重点关注 SRC-3 对 miR-34a 的调节及其在癌症进展中的作用。有趣的是，SRC-3 作为抑制 miR-34a 表达的“辅阻遏物”而不是“共激活剂”发挥作用。乳腺癌中SRC-3的表达与肿瘤分级和分期呈正相关，但与miR-34a的表达呈负相关，提示SRC-3和miR-34a的表达与乳腺癌的疾病状态之间存在因果关系。这是 SRC-3 的“辅阻遏物”功能的首次报道，SRC-3 作为“辅阻遏物”抑制 miR-34a 表达的意义和机制仍有待确定。我们的中心假设是，SRC-3 以背景和信号依赖方式作为“辅阻遏物”发挥作用，抑制 miR-34a 表达并促进 CSC 活性。本申请的目的是确定决定 SRC-3“辅阻遏物”功能的机制，并证明 SRC-3-miR-34a 通路在 CSC 中的作用。我们将通过追求两个目标来实现我们的目标。目标 1. 鉴定致癌共激活因子 SRC-3 的“辅阻遏物”活性。尽管 miR-34a 作为肿瘤抑制因子很重要，但在 CSC 中如何抑制 miR-34a 的表达尚不清楚。为了了解 miR-34a 如何被 SRC-3 抑制，转录阻遏调节因子 X1 (RFX1) 和 SRC-3 在 S505 处的去磷酸化被确定为 SRC-3“辅阻遏”功能的潜在决定因素。这是致癌“辅激活因子”SRC-3 的“辅阻遏物”活性的第一份报告，我们的目标是阐明 SRC-3 在 S505 处的去磷酸化决定其与 RFX1 一起发挥“辅阻遏物”功能以抑制 miR 的机制-34a 表达式。目标 2. 定义 SRC-3“辅阻遏物”活性的功能。 MiR-34a 是一种重要的肿瘤抑制因子，可抑制 CSC 功能。 SRC-3 和 RFX1 被确定为 miR-34a 表达的新型抑制剂。我们的目的是证明 SRC-3 与 RFX1 的“辅阻遏物”活性通过抑制 miR-34a 表达来促进 CSC 功能。我们的研究极具创新性且意义重大。它表明 SRC-3 在富含 CSC 的生态位中充当“辅阻遏物”，通过抑制 miR-34a 来促进 CSC 功能。它首次揭示了 SRC-3 的“辅阻遏物”功能依赖于转录阻遏物 RFX1 及其自身的去磷酸化。我们的研究揭示了一种新的“辅阻遏物”活性，它控制着 CSC 中 SRC-3 的功能。这是朝着我们确定可靶向 SRC-3 CSC 途径的长期目标迈出的重要一步，该途径将有助于开发抗 CSC 疗法，以改善癌症患者的治疗反应和生存。