Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France.
Genomic Facility, Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France.
Cell Mol Gastroenterol Hepatol. 2023;15(3):689-715. doi: 10.1016/j.jcmgh.2022.10.017. Epub 2022 Nov 8.
BACKGROUND & AIMS: Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive.
We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples.
We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies.
Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.
Axin1 是 Wnt/β-catenin 信号通路的负调控因子，具有抑癌功能。Wnt 通路在肠道中具有重要作用，无论是在稳态还是癌症中，但 Axin1 的作用仍不清楚。
我们评估了 Axin1 在正常肠道稳态中的作用，使用了对照、上皮特异性、Axin1 敲除（Axin1）和 Axin2 敲除小鼠。我们评估了 Axin1 在化学诱导的结直肠肿瘤发生和葡聚糖硫酸钠诱导的结肠炎中的肿瘤抑制功能，并通过全基因组 RNA 测序进行了比较基因表达谱分析。然后，在 2239 例临床结直肠癌（CRC）样本数据库中测试了依赖 Axin1 的基因表达特征的临床相关性。
我们发现 Axin1 对于正常肠道稳态是可有可无的，并且与 Axin2 对于 Wnt 通路的下调是冗余的。肠上皮细胞中的 Axin1 缺失使小鼠更容易发生化学诱导的结肠癌，但通过减弱促炎程序的诱导，减少了葡聚糖硫酸钠诱导的结肠炎。RNA-seq 分析确定了一个由 Axin1 控制的干扰素 γ/T-helper1 免疫程序，该程序增强了炎症反应并预防 CRC。Axin1 依赖性基因表达特征被应用于人类 CRC 样本，并确定了一组可能对免疫检查点阻断治疗敏感的患者。
我们的研究在体内建立了 Axin1 与 Axin2 对于 Wnt 下调具有冗余功能，并推断出 Axin1 的新作用。生理上，Axin1 通过干扰素 γ/Th1 程序刺激肠道炎症，从而阻止肿瘤生长。与 T 细胞介导的作用相关，结肠 Axin1 特征为 CRC 提供了治疗前景。
