The mutational genetic landscape of colorectal cancer has been extensively characterized, however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. Implications: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.

中文翻译：

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芳烃受体的缺失促进 ApcS580/+ 中的结肠肿瘤发生；KrasG12D/+ 小鼠

结直肠癌的突变遗传景观已被广泛表征，然而，“合作反应基因”调节癌症“驱动”基因功能的能力仍然很大程度上未知。在这项研究中，我们研究了配体激活的转录因子芳烃受体 (AhR) 在调节结肠致癌信号中的作用。我们表明，肠上皮细胞靶向 AhR 敲除 (KO) 促进了含有 ApcS580/+ 的结肠干/祖细胞的扩增和克隆形成能力；通过上调 Wnt 信号传导的 KrasG12D/+ 突变。肠道上皮细胞中AhR的缺失增加了细胞增殖，降低了小鼠存活率，并促进了小鼠盲肠和结肠肿瘤的发生。机械地，Lgr5 单倍体不足诱导的 Wnt 信号拮抗作用减弱了 AhR KO 对盲肠和结肠肿瘤发生的影响。启示：我们的研究结果表明，AhR 信号传导至少通过抑制 Wnt 信号传导在遗传诱导的结肠肿瘤发生中起保护作用，并为将 AhR 作为癌症预防和治疗的治疗靶点提供了理论基础。