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Axin1 protects colon carcinogenesis by an immune-mediated effect

Open AccessPublished:November 07, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.10.017
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      Background & Aims

      Axin1 is a negative regulator of 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.

      Methods

      We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific Axin1-knockout mice (Axin1ΔIEC) and Axin2-knockout mice. We evaluated the tumor suppressor function of Axin1 during chemically induced colorectal tumorigenesis and DSS-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature was then tested in a database of 2,239 clinical colorectal cancer (CRC) samples.

      Results

      We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for the Wnt pathway downregulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced DSS-induced colitis by attenuating the induction of a pro-inflammatory program. RNA-seq analyses identified an IFNγ/Th1 immune program controlled by Axin1 that enhances the inflammatory response and protects against colorectal cancer. 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.

      Conclusions

      Our study establishes, in vivo, that Axin1 have redundant function with Axin2 for Wnt downregulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an IFNγ/Th1 program that prevent tumor growth. Linked to its T-cell mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.

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