The miR-20/c-Myc/E2F Regulatory Axis is Critical for the Tumor Promoting Activity of Inflammatory Fibroblasts in Colitis-Associated Cancer

miR-20/c-Myc/E2F 调节轴对于结肠炎相关癌症中炎症成纤维细胞的肿瘤促进活性至关重要

• 批准号: 10388030
• 负责人: Emina HUI-NA Huang
• 金额: $ 55.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388030
• 关键词: Affect; Apoptosis; Cells; Chronic; Colitis; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complex; Data; Development; Disease; Disease Progression; Down-Regulation; Dysplasia; Epithelial; Family; Feedback; Fibroblasts; Fright; General Population; Genes; Goals; Health; Heterogeneity; IL8 gene; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Knowledge; Learning; Link; Malignant Neoplasms; Measures; Medical; Mesenchymal; Messenger RNA; MicroRNAs; Mission; Molecular; Neoplasm Metastasis; Oncogenic; Organoids; Outcome; Pathogenesis; Patients; Phenotype; Population; Prevention strategy; Process; Public Health; Reactive Oxygen Species; Reporting; Research; Risk; Risk Factors; Role; TP53 gene; Testing; Tissues; Transcriptional Regulation; Tumor Promotion; Tumorigenicity; Ulcerative Colitis; United States National Institutes of Health; base; c-myc Genes; cancer cell; cancer type; chemokine; chronic inflammatory disease; colitis associated cancer; colon cancer prevention; colon tumorigenesis; defined contribution; diagnostic biomarker; genotoxicity; high risk; human tissue; in vivo; innovation; interstitial; knock-down; member; overexpression; predictive modeling; prevent; preventive intervention; prognostic tool; senescence; single cell mRNA sequencing; subcutaneous; targeted agent; transcription factor; tumor; tumor progression; tumorigenesis; tumorigenic

SUMMARY Inflammation is a risk factor for several types of cancer. For example, in ulcerative colitis (UC), a disease of chronic inflammation of the colon, the risk of developing colitis-associated cancer of the colon (CAC) is 3 to 5- fold higher than the risk in the general population of developing sporadic colorectal cancer (CRC). Worse, there are no curative CAC-preventing or CAC-reversing options for UC patients, and the pathogenesis of CAC is unclear. The precise oncogenic triggers in this complex milieu remain mysterious and are therefore difficult to target. Given this situation, our long-term goal is to understand the pathogenesis of colitis and CAC such that development of preventive interventions becomes more feasible. We recently reported that colitis-associated fibroblasts and cancer-associated fibroblasts from UC patients secrete elevated levels of CXCL8 (an inflammatory mediator), that CXCL8 levels are negatively regulated by a miRNA, miR-20a, and that miR-20a is, at least in part, responsible for the modulation of CXCL8 secretion in interstitial fibroblasts. miR-20a is known to be modulated by c-Myc via interaction with the E2F family of transcription factors. However, in contrast to the colon epithelia our data indicate that low miR-20a and low c-Myc levels in colitic fibroblasts increase tumorigenicity. To resolve this conundrum, the overall objective of this application, is to determine the contribution of fibroblast miR-20, a member of the miR-17 family, to the pathogenesis of CAC. Our central hypothesis is that downregulation of the miR-20a/c-Myc/E2F axis is critical for the tumor-promoting activity of colon interstitial fibroblasts. To test these relationships, we will pursue three Aims: 1) To define the contribution of miR-20 in the colitic stromal fibroblasts to tumorigenesis, 2) To delineate the roles of fibroblast c-Myc and E2F7/8 on miR-20 and tumor-promotion, and 3) To identify the stromal fibroblast populations associated with disease progression and to determine their use as prognostic tools. The approach is innovative as it uses exclusively human tissue isolates, focuses on mechanistic investigation of the miR-20a, c-Myc, and E2F7/8 relationships, and reconciles fibroblast subpopulations at the single cell level for their contributions to the pathogenesis of CAC. The research is significant as it provides a molecular basis for the tumor-promoting activity of the stroma, which will benefit the one million US colitis patients at risk for CAC. In addition, our findings will be applicable for any chronic inflammatory process for which the stroma provides additional avenues for intervention.

摘要 炎症是几种癌症的危险因素。例如，在溃疡性结肠炎(UC)中，一种 慢性结肠炎，罹患结肠炎相关性结肠癌(CAC)的风险为3至5 比普通人群罹患散发性结直肠癌(CRC)的风险高出一倍。更糟糕的是，在那里 对于UC患者来说，CAC没有根治的预防或逆转CAC的选择，CAC的发病机制是 不清楚。在这个复杂的环境中，确切的致癌触发因素仍然是个谜，因此很难 目标。鉴于这种情况，我们的长期目标是了解结肠炎和CAC的发病机制，以便 制定预防性干预措施变得更加可行。我们最近报道了与结肠炎相关的 UC患者成纤维细胞和肿瘤相关成纤维细胞分泌高水平的CXCL8(AN 炎症介质)，CXCL8水平受miRNA、miR-20a负向调节，而miR-20a是， 至少部分参与了间质成纤维细胞分泌CXCL8的调控。已知MIR-20a C-Myc通过与E2F转录因子家族的相互作用进行调节。然而，与 结肠上皮我们的数据表明结肠炎成纤维细胞中miR-20a和c-Myc的低水平增加 致瘤性。为了解决这个难题，此应用程序的总体目标是确定 MiR-17家族成员成纤维细胞miR-20在CAC发病机制中的作用我们的中央 假说认为miR-20a/c-Myc/E2F轴的下调对其促肿瘤活性至关重要 结肠间质成纤维细胞。为了测试这些关系，我们将追求三个目标：1)定义贡献 MiR-20在结肠间质成纤维细胞中的表达与肿瘤发生的关系，2)探讨成纤维细胞c-Myc和 E2F7/8对miR-20和肿瘤促进作用的影响，以及3)鉴定与 疾病进展，并确定其作为预后工具的使用。这种方法是创新的，因为它使用了 专门分离人组织，重点研究miR-20a、c-Myc和E2F7/8的机制 关系，并协调成纤维细胞亚群在单细胞水平上对 CAC的发病机制。这项研究具有重要意义，因为它为其促肿瘤活性提供了分子基础。 这将使100万有CAC风险的美国结肠炎患者受益。此外，我们的发现将 适用于间质为其提供额外途径的任何慢性炎症过程 干预。