Dioxin Receptor Adjusts Liver Regeneration After Acute Toxic Injury and Protects Against Liver Carcinogenesis.

ABSTRACT: The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation and pluripotency in normal and transformed cells. Here, AhR-null mice (AhR-/-) were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting the expansion of stem-like cells and the expression of pluripotency genes. Short-term CCl₄ liver damage was earlier and more efficiently repaired in AhR-/- than in AhR+/+ mice. Stem-like CK14?+?and TBX3?+?and pluripotency-expressing OCT4?+?and NANOG?+?cells expanded sooner in AhR-/- than in AhR+/+ regenerating livers. Stem-like side population cells (SP) isolated from AhR-/- livers had increased ?-catenin (?-Cat) signaling with overexpression of Axin2, Dkk1 and Cyclin D1. Interestingly, ?-Cat, Axin2 and Dkk1 also increased during regeneration but more notably in AhR-null livers. Liver carcinogenesis induced by diethylnitrosamine (DEN) produced large carcinomas in all AhR-/- mice but mostly premalignant adenomas in less than half of AhR+/+ mice. AhR-null tumoral tissue, but not their surrounding non-tumoral parenchyma, had nuclear ?-Cat and Axin2 overexpression. OCT4 and NANOG were nevertheless similarly expressed in AhR+/+ and AhR-/- lesions. We suggest that AhR may serve to adjust liver repair and to block tumorigenesis by modulating stem-like cells and ?-Cat signaling.

SUBMITTER: Moreno-Marin N 

PROVIDER: S-EPMC5585208 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature