Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Garvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Cell Mol Gastroenterol Hepatol. 2019;7(4):819-839. doi: 10.1016/j.jcmgh.2019.01.009. Epub 2019 Mar 2.
BACKGROUND & AIMS: The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.
We generated knockout mice with deletion of Mcc in the colonic/intestinal epithelial cells (Mcc) or in the whole body (Mcc). Drug-induced lesions were analyzed by transcriptome profiling (at 10 weeks) and histopathology (at 20 weeks). Cell-cycle phases and DNA damage proteins were analyzed by flow cytometry and Western blot of hydrogen peroxide-treated mouse embryo fibroblasts.
Transcriptome profiling of the lesions showed a strong response to colon barrier destruction, such as up-regulation of key inflammation and cancer-associated genes as well as 28 interferon γ-induced guanosine triphosphatase genes, including the homologs of Crohn's disease susceptibility gene IRGM. These features were shared by both Mcc-expressing and Mcc-deficient mice and many of the altered gene expression pathways were similar to the mesenchymal colorectal cancer subtype known as consensus molecular subtype 4 (CMS4). However, Mcc deletion was required for increased carcinogenesis in the lesions, with adenocarcinoma in 59% of Mcc compared with 19% of Mcc-expressing mice (P = .002). This was not accompanied by hyperactivation of β-catenin, but Mcc deletion caused down-regulation of DNA repair genes and a disruption of DNA damage signaling.
Loss of Mcc may promote cancer through a failure to repair inflammation-induced DNA damage. We provide a comprehensive transcriptome data set of early colorectal lesions and evidence for the in vivo significance of MCC silencing in colorectal cancer.
炎症促进癌症的早期事件仍未完全明确。MCC 基因在结肠炎相关和散发性结肠肿瘤中因启动子甲基化而沉默，但在癌前病变或息肉中的功能意义尚不清楚。在此，我们旨在确定 Mcc 缺失对小鼠近端结肠中与炎症相关的细胞通路和癌变的影响。
我们生成了在结肠/肠上皮细胞（Mcc）或全身（Mcc）中缺失 Mcc 的敲除小鼠。通过转录组谱分析（第 10 周）和组织病理学（第 20 周）分析药物诱导的病变。通过流式细胞术和过氧化氢处理的小鼠胚胎成纤维细胞的 Western blot 分析细胞周期阶段和 DNA 损伤蛋白。
病变的转录组谱分析显示出对结肠屏障破坏的强烈反应，例如上调关键炎症和癌症相关基因以及 28 种干扰素 γ 诱导的鸟苷三磷酸酶基因，包括克罗恩病易感性基因 IRGM 的同源物。这些特征在表达和缺失 Mcc 的小鼠中均存在，并且许多改变的基因表达途径与称为共识分子亚型 4（CMS4）的间充质结直肠癌亚型相似。然而，Mcc 缺失是病变中致癌作用增加所必需的，Mcc 缺失小鼠的腺癌发生率为 59%，而表达 Mcc 的小鼠为 19%（P=.002）。这并没有伴随着 β-连环蛋白的过度激活，而是 Mcc 缺失导致 DNA 修复基因下调和 DNA 损伤信号中断。
Mcc 的缺失可能通过无法修复炎症诱导的 DNA 损伤来促进癌症。我们提供了早期结直肠病变的综合转录组数据集，并为 MCC 沉默在结直肠癌中的体内意义提供了证据。
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