Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids.
Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids.
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DOI：
10.18632/oncotarget.28058
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发表时间：
2021-09-14
期刊：
影响因子：
--
通讯作者：
Casey G
中科院分区：
文献类型：
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作者：
Devall M;Dampier CH;Eaton S;Ali MW;Díez-Obrero V;Moratalla-Navarro F;Bryant J;Jennelle LT;Moreno V;Powell SM;Peters U;Casey G
烟草烟雾和红肉/加工肉类是众所周知的结直肠癌 (CRC) 危险因素。大多数研究都集中在流行病学研究中的正常结肠活检或体外结直肠癌细胞系的治疗。这些研究常常受到自我报告数据准确性的挑战，或者就CRC细胞系而言，样本量小以及与处于危险中的正常组织缺乏关系的挑战。为了解决其中一些局限性，我们对来自正常结肠活检的 37 个独立类器官系进行了 24 小时的代表性致癌物混合物处理。机器学习算法应用于批量 RNA 测序，并揭示了结肠类器官中细胞组成的变化。我们鉴定了 738 个与致癌物暴露有关的差异表达基因。网络分析确定了显着不同的共表达模块，其中包括与 MSI-H 肿瘤生物学相关的基因，以及先前通过全基因组关联研究与 CRC 相关的基因。我们的研究有助于更好地确定吸烟和红肉/加工肉中代表性致癌物对正常结肠上皮细胞以及 MSI-H CRC 亚型病因学的分子影响，并表明遗传性和环境性 CRC 风险所涉及的分子机制之间存在重叠。
Tobacco smoke and red/processed meats are well-known risk factors for colorectal cancer (CRC). Most research has focused on studies of normal colon biopsies in epidemiologic studies or treatment of CRC cell lines in vitro. These studies are often constrained by challenges with accuracy of self-report data or, in the case of CRC cell lines, small sample sizes and lack of relationship to normal tissue at risk. In an attempt to address some of these limitations, we performed a 24-hour treatment of a representative carcinogens cocktail in 37 independent organoid lines derived from normal colon biopsies. Machine learning algorithms were applied to bulk RNA-sequencing and revealed cellular composition changes in colon organoids. We identified 738 differentially expressed genes in response to carcinogens exposure. Network analysis identified significantly different modules of co-expression, that included genes related to MSI-H tumor biology, and genes previously implicated in CRC through genome-wide association studies. Our study helps to better define the molecular effects of representative carcinogens from smoking and red/processed meat in normal colon epithelial cells and in the etiology of the MSI-H subtype of CRC, and suggests an overlap between molecular mechanisms involved in inherited and environmental CRC risk.