The role of butyrate-producing bacteria in CIMP colorectal cancer tumorigenesis

丁酸产生菌在 CIMP 结直肠癌肿瘤发生中的作用

基本信息

批准号：
9309766
负责人：
Brent Lamont Williams
金额：
$ 38.67万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309766
关键词：
Acetates Antineoplastic Agents Bacteria Biopsy Butyrates Cancer Etiology Cessation of life Colon Colonoscopy Colorectal Cancer Communities CpG Island Methylator Phenotype CpG Islands Development Diagnostic Diet Dietary Fiber Economic Burden Electrons Epidermal Growth Factor Receptor Epigenetic Process Event Exhibits Fatty Acids Fermentation Fiber Genes Growth High-Throughput Nucleotide Sequencing Histone Deacetylase Histone Deacetylase Inhibitor Hypermethylation Individual Intestines Investigation Knowledge Large Intestine Large Intestine Carcinoma Lead Lesion MEKs Mass Fragmentography Measures Mediating Medium chain fatty acid Metagenomics Methylation Mismatch Repair Molecular Morphology Mucous Membrane Mus Neoplasms Normal tissue morphology Pathway interactions Patients Phylogenetic Analysis Play Polyps Population Precancerous Polyp Preventive treatment Promoter Regions Propionates Public Health Quantitative Evaluations Ras/Raf Research Risk Risk Assessment Role Surveys Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice Transgenic Organisms Tumor Suppression Tumor Tissue United States Volatile Fatty Acids acronyms cohort epidemiology study gut microbiome gut microbiota insight ionization metagenome microbial microbiome microbiota molecular phenotype mouse model promoter public health relevance rRNA Genes rapid growth reconstruction senescence tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY The serrated pathway to colorectal carcinoma (CRC) accounts for 35% of all CRC. A subset of lesions arising along this pathway are characterized by methylation of CPG islands in the promoters of genes involved in tumor suppression and mismatch repair leading to their epigenetic silencing. Accordingly, this group of tumors is known by the acronym CIMP (CpG island methylator phenotype). Epidemiological studies suggest that serrated lesions leading to CIMP CRCs may be more likely to be missed with colonoscopy perhaps due to their predominance in the proximal colon, morphology, or rapid growth rate. CIMP tumors have also been associated with an increased risk of CRC-related death. Despite the public health importance, the underlying cause of these aberrant epigenetic changes remains unknown. Identification of factors contributing to aberrant methylation in CIMP could lead to new strategies for risk assessment and preventative therapeutic interventions. We recently conducted a preliminary study to examine the role of the microbiome in CIMP CRCs. Our research suggests that prominent butyrate-producing bacterial (BPB) populations and the butyrate they produce are deficient in CIMP compared to Non-CIMP CRCs. We hypothesize that deficiency in colonic butyrate, a bacterial metabolite of fiber fermentation with known anti-neoplastic and epigenetic effects, is the primary cause of abnormal CpG island methylation in CIMP CRCs. To test this hypothesis, we will characterize biopsies from patients with CIMP and Non-CIMP tumors and pursue mechanistic studies in a transgenic mouse model. In Aim 1, we will use high-throughput sequencing of the bacterial 16S rRNA gene, to evaluate group-specific differences in the microbiota between patients with CIMP and Non-CIMP tumors and investigate functional differences between the CIMP and Non-CIMP tissues, including synthesis of butyrate and other short-chain fatty acids, such as propionate and acetate. In Aim 2, we will quantitate and compare concentrations of butyrate and other fatty acids directly in tumors and normal tissue from patients with CIMP and Non-CIMP tumors. In Aim 3, we will interrogate the transgenic HBUS mouse model of serrated tumorigenesis to investigate the functional consequences of dietary fiber deficiency and deficient BPB populations and butyrate on tumor progression and CIMP. At the conclusion of these studies, we will have expanded our knowledge of the role of the microbiota in different molecular phenotypes of CRC and provided evidence for or against a causal role for BPB and butyrate deficiency in aberrant CpG island methylation found in CIMP tumors.

项目摘要结直肠癌（CRC）的锯齿途径占所有CRC的35％。出现的病变子集沿着该途径的特征是在涉及的基因启动子中甲基化CpG岛肿瘤抑制和不匹配的修复导致其表观遗传沉默。因此，这组肿瘤通过首字母缩写CIMP（CpG岛甲基表型）知道。流行病学研究表明导致CIMP CRC的锯齿状病变可能更有可能因其结肠镜检查而错过近端结肠，形态或快速生长速率的优势。 CIMP肿瘤也已经与CRC相关死亡的风险增加有关。尽管公共健康的重要性，但基础这些异常表观遗传变化的原因仍然未知。识别导致异常的因素 CIMP中的甲基化可能导致风险评估和预防治疗的新策略干预措施。我们最近进行了一项初步研究，以检查微生物组在CIMP中的作用 CRC。我们的研究表明，著名的丁酸酯产生细菌（BPB）人群和丁酸酯与非CIMP CRC相比，它们产生的CIMP缺乏。我们假设结肠缺乏丁酸酯是一种具有已知抗塑性和表观遗传作用的纤维发酵的细菌代谢产物，是 CIMP CRC中CPG岛甲基化异常的主要原因。为了检验这一假设，我们将表征来自CIMP和非CIMP肿瘤患者的活检，并在转基因中进行机械研究鼠标模型。在AIM 1中，我们将使用细菌16S rRNA基因的高通量测序来评估 CIMP和非CIMP肿瘤患者的菌群中群体特异性差异并研究 CIMP和非CIMP组织之间的功能差异，包括丁酸酯和其他的合成短链脂肪酸，例如丙酸酯和乙酸。在AIM 2中，我们将定量和比较丁酸酯和其他脂肪酸的浓度直接在肿瘤中的CIMP患者和正常组织中和非细胞肿瘤。在AIM 3中，我们将询问锯齿状的转基因HBU小鼠模型肿瘤发生以研究饮食纤维缺乏和BPB缺乏的功能后果种群和丁酸肿瘤进展和CIMP。这些研究结束时，我们将有扩展了我们对菌群在不同分子表型中的作用的了解，并提供了发现异常CpG岛甲基化的BPB和丁酸缺乏的因果作用的证据在CIMP肿瘤中。