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.

项目概要锯齿状途径导致结直肠癌 (CRC) 占所有 CRC 的 35%。出现病变的子集沿着这条途径的特征是参与相关基因的启动子中的 CPG 岛甲基化肿瘤抑制和错配修复导致其表观遗传沉默。据此，这组肿瘤缩写为 CIMP（CpG 岛甲基化表型）。流行病学研究表明结肠镜检查可能更容易漏掉导致 CIMP CRC 的锯齿状病变，这可能是由于其近端结肠占优势，形态或生长速度较快。 CIMP肿瘤也被与结直肠癌相关死亡风险增加有关。尽管对公共卫生很重要，但潜在的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 中的甲基化可能会带来风险评估和预防性治疗的新策略干预措施。我们最近进行了一项初步研究，探讨微生物组在 CIMP 中的作用 CRC。我们的研究表明，重要的丁酸产生细菌（BPB）群体和丁酸与非 CIMP CRC 相比，它们生产的 CIMP 缺乏。我们假设结肠缺乏丁酸盐是一种纤维发酵的细菌代谢物，具有已知的抗肿瘤和表观遗传作用，是 CIMP CRC 中 CpG 岛甲基化异常的主要原因。为了检验这个假设，我们将描述对 CIMP 和非 CIMP 肿瘤患者进行活检，并在转基因中进行机制研究鼠标模型。在目标 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 肿瘤患者之间微生物群的群体特异性差异并进行调查 CIMP 和非 CIMP 组织之间的功能差异，包括丁酸和其他物质的合成短链脂肪酸，例如丙酸和乙酸。在目标 2 中，我们将量化并比较 CIMP 患者肿瘤和正常组织中丁酸和其他脂肪酸的浓度和非 CIMP 肿瘤。在目标 3 中，我们将研究锯齿状的转基因 HBUS 小鼠模型。肿瘤发生研究膳食纤维缺乏和 BPB 缺乏的功能后果人群和丁酸盐对肿瘤进展和 CIMP 的影响。在这些研究结束时，我们将得到扩展了我们对微生物群在 CRC 不同分子表型中的作用的了解，并提供了发现支持或反对 BPB 和丁酸缺乏在异常 CpG 岛甲基化中的因果作用的证据在 CIMP 肿瘤中。