El receptor de dioxina en poliploidía, regeneración y metabolismo hepáticointeracción con la vía de señalización PI3K/AKT y WNT/β-Catenina

Abstract

Aryl hydrocarbon receptor depletion induces undifferentiation and pluripotency. AhR-null mice were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting stem-like cells expansion and pluripotency genes expression. 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-/- regenerating livers. Moreover stem-like side population cells (SP) isolated from AhR-/- livers had increased β-catenin signaling. Liver carcinogenesis induced by DEN produced large carcinomas in all AhR-/- mice but mostly premalignant adenomas in less than half of AhR+/+ mice and AhR-null tumoral tissue had nuclear β-Catenin and Axin2 overexpression. We suggest that AhR may serve to adjust liver repair and to block tumorigenesis in the liver. Importantly, liver polyploidization is fundamental for cell growth, metabolic competence, and tumor development. We report that AhR regulates the diploid to-polyploid conversion taking place during the preweaning-to-adult maturation of mouse liver. AhR-null livers had smaller hepatocytes, hypercellularity and enhanced proliferative potential. AhR-/- livers showed compromised polyploidy and enlarged centrosomes. This phenotype could involve PI3K, ERK, and Wnt/β-Catenin signaling pathways which were persistently upregulated in preweaning and adult AhR-/- liver, likely resulting in their enhanced mTOR activation. Additionally AhR-/- mice had a deregulation of mitochondrial oxidative phosphorylation intermediates succinate and fumarate. Thus, AhR would be required for the diploid to polyploid transition and since polyploidization is essential for adult liver function and tumor progression, selective AhR modulators could be interesting therapeutic tools in the liver.