Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract

The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice were generated that lacked Runx1 expression in epithelial cells of the GI tract. These mice were crossed onto the ApcMin background, sacrificed, and their intestinal tumor phenotypes were compared with ApcMin Runx1 wildtype control mice. Apc-wildtype Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wildtype mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium, to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc-wildtype mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1 deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. A total of 8 colon tissue RNA samples were analyzed, comprising 4 colon samples from wild-type mice (Villin-Cre negative / Runx1-floxed) and 4 colon samples from mice that lack epithelial expression of Runx1 (Villin-Cre positive/Runx1-floxed).Runx1转录因子（Runx1 transcription factor）通过调控干细胞/祖细胞群与分化进程，在组织稳态维持中发挥关键作用。此前已有研究证实Runx1对结肠分泌细胞谱系上皮分化的调控效应。本研究旨在探讨Runx1在胃肠道上皮细胞肿瘤发生中的作用。本研究构建了胃肠道上皮细胞中Runx1表达缺失的条件性敲除小鼠（conditional knockout mice），将其与ApcMin背景小鼠杂交后处死，并将其肠道肿瘤表型与ApcMin背景下Runx1野生型对照小鼠进行对比；同时也检测了Apc野生型、Runx1突变小鼠的肿瘤发生情况。收集Runx1敲除小鼠与野生型小鼠的结肠组织，开展全基因组mRNA表达分析（genome-wide mRNA expression analyses），并针对全结肠及结肠上皮组织进行基因特异性定量反转录PCR（quantitative RT-PCR），以鉴定Runx1的靶基因。研究结果显示，肠道上皮细胞中Runx1缺失可显著促进ApcMin小鼠的肿瘤发生。值得注意的是，在Apc野生型小鼠中，上皮Runx1缺失即可独立诱发肿瘤形成。Runx1缺失与炎症、肠道代谢相关基因的全局表达改变密切相关，同时也与反映转移表型及不良预后的基因集特征相关。对Runx1缺失的结肠上皮进行基因特异性分析发现，与干细胞/祖细胞群扩增相关的基因表达水平显著上调。本研究结果表明Runx1是胃肠道肿瘤的新型抑癌基因，证实其在维持肠道干细胞/祖细胞群与胃肠道上皮分化之间的平衡中发挥重要作用。本研究共分析8份结肠组织RNA样本，其中4份来自野生型小鼠（Villin-Cre阴性/Runx1-floxed），另外4份来自上皮细胞Runx1表达缺失的小鼠（Villin-Cre阳性/Runx1-floxed）。