Inactivation of Irf1 causes susceptibility to colitis-associated colorectal cancer

The incidence of colorectal cancer (CRC) is increased in patients afflicted by inflammatory bowel diseases (IBD) The cellular and molecular mechanisms that link chronic inflammation of the gut and increased CRC susceptibility are poorly understood. Risk of IBD is strongly influenced by genetic factors, including the IBD5 locus (5q31), harboring the IRF1 gene. A cause to effect relationship between chronic inflammation and CRC, and a possible role of IRF1 were studied in Irf1-/- mutant mice in a model of colitis associated CRC (CA-CRC) induced by azoxymethane and the irritant dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation, enhanced crypt cells proliferation and reduced tissue repair in Irf1-/- mutants, and this prior to appearance of tumors. A considerable infiltration of leukocytes is seen at this early stage in Irf1-/- colons, this infiltrate being composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells, mast cells, and CD3+ lymphoid cells. Studies in bone marrow chimeras show that differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable by hematopoietic cells. Studies in human datasets confirm that transcripts signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with CRC. In addition, IRF1 expression in the colon is significantly decreased in late stage CRC (stages 3, 4) associated with poorer prognosis. These studies suggest that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ in gut establishing microbial-driven chronic inflammation and possibly creating a tumor promoting environment.

炎症性肠病（inflammatory bowel diseases, IBD）患者的结直肠癌（colorectal cancer, CRC）发病率升高，但将肠道慢性炎症与结直肠癌易感性增加联系起来的细胞与分子机制仍不甚明确。IBD的发病风险受遗传因素显著影响，其中包括携带IRF1基因的IBD5基因座（5q31）。本研究在氧化偶氮甲烷与刺激性试剂硫酸葡聚糖诱导的结肠炎相关结直肠癌（colitis associated CRC, CA-CRC）模型中，针对Irf1基因敲除突变小鼠（Irf1-/- mutant mice）探究了慢性炎症与结直肠癌之间的因果关系，以及IRF1可能发挥的作用。研究发现，Irf1缺失会使小鼠对CA-CRC的易感性升高，表现为肿瘤发病更早、肿瘤数量增多并快速导致小鼠死亡。对结肠组织的转录组测序（RNA-seq）与免疫染色结果显示，在肿瘤出现之前，Irf1-/-突变体小鼠的结肠炎症加剧、隐窝细胞增殖增强且组织修复能力下降。在此早期阶段，Irf1-/-小鼠的结肠中可见大量白细胞浸润，浸润细胞主要由促炎性Gr1+Cd11b+髓系细胞、肥大细胞以及CD3+淋巴样细胞构成。骨髓嵌合体实验表明，Irf1-/-小鼠与B6野生型对照小鼠对CA-CRC的易感性差异可完全通过造血细胞进行转移。对人类数据集的分析证实，Irf1-/-小鼠在AOM/DSS诱导下产生的转录特征，在IBD与CRC患者的临床标本中显著富集。此外，晚期（3、4期）结直肠癌患者的结肠组织中IRF1表达水平显著降低，且与不良预后相关。上述研究表明，IRF1表达的部分或完全缺失会改变肠道原位免疫细胞的类型、数量与功能，进而建立微生物驱动的慢性炎症状态，并可能形成促肿瘤微环境。