A C/EBPα-Wnt connection in gut homeostasis and carcinogenesis.
Julian HeubergerUndine HillSusann FörsterKarin ZimmermannVictoria MalchinAnja A KühlUlrike SteinMichael ViethWalter BirchmeierAchim LeutzPublished in: Life science alliance (2018)
We explored the connection between C/EBPα (CCAAT/enhancer-binding protein α) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPα 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/EBPα was absent in the nuclear β-catenin-positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPα KO in murine gut epithelia increased tumor volume. C/EBPα 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 β-catenin in organoids attenuated C/EBPα expression, and ectopic C/EBPα expression in HCT116 cells abrogated proliferation. C/EBPα expression accompanied differentiation of the colon cancer cell line Caco-2, whereas β-catenin stabilization suppressed C/EBPα. These data suggest homeostatic and oncogenic suppressor functions of C/EBPα in the gut by restricting Wnt signaling.
Keyphrases
- stem cells
- binding protein
- gene expression
- cell proliferation
- poor prognosis
- endothelial cells
- induced apoptosis
- epithelial mesenchymal transition
- genome wide
- cell cycle arrest
- transcription factor
- dna methylation
- copy number
- long non coding rna
- artificial intelligence
- big data
- diabetic rats
- deep learning
- mesenchymal stem cells