A C/EBPa–Wnt connection in gut homeostasis and carcinogenesis

We explored the connection between C/EBPa (CCAAT/enhancer binding protein a) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPa was expressed in human and murine intestinal epithelia in the transit amplifying region of the crypts and was absent in intestinal stem cells and Paneth cells with activated Wnt signaling. In human colorectal cancer and murine APCMin/+ polyps, C/EBPa was absent from nuclear ß-catenin–positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPa KO in murine gut epithelia increased tumor volume. C/EBPa deletion extended the S-phase cell zone in intestinal organoids and activated typical proliferation gene expression signatures, including that of Wnt target genes. Genetic activation of ß-catenin in organoids attenuated C/EBPa expression. Comparing gene expression of wild type and C/EBPa KO organoids by RNA sequencing aimed to identify C/EBPa dependent alterations in gene expression. Overall design: These data suggest homeostatic and oncogenic suppressor functions of C/EBPa in the gut by restricting Wnt signaling.

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Heuberger J, Hill U, Förster S, Zimmermann K, Malchin V, Kühl AA, Stein U, Vieth M, Birchmeier W, Leutz A