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

Nuria Moreno-Marín,Pedro M Fernández-Salguero,Antonio Morales-Hernández,Eva Barrasa,Gerardo Blanco-Fernández,Jaime M Merino,Beroé Paniagua

doi:10.1038/s41598-017-10984-w

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 β-catenin (β-Cat) signaling with overexpression of Axin2, Dkk1 and Cyclin D1. Interestingly, β-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 β-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 β-Cat signaling.

Highlights

The aryl hydrocarbon/dioxin receptor (AhR) interacts with signalling pathways controlling the cell response to toxic and carcinogenic compounds and relevant physiological functions[19, 20]
Quantification of necrotic regions revealed that regeneration took place faster and more efficiently in aryl hydrocarbon receptor (AhR)−/− mice since very few necrotic lesions remained at 72 h from treatment and their parenchyma was fully restored by 4 days
AhR expression transiently increased during the repair process in CCl4 exposed AhR+/+ mice, reaching a maximum at 72 h in cells located close to the central vein to decrease to very low levels at 4 days (Fig. 1b)

Summary

Introduction

The aryl hydrocarbon/dioxin receptor (AhR) interacts with signalling pathways controlling the cell response to toxic and carcinogenic compounds and relevant physiological functions[19, 20]. We have used AhR wild type (AhR+/+) and AhR-null (AhR−/−) mice to investigate how AhR deficiency affects the activation of stem-like and pluripotent cells in the liver during regeneration after acute exposure to the hepatotoxin CCl4 and in hepatic tumors induced by the carcinogen diethylnitrosamine (DEN). We have found that AhR depletion improved liver regeneration and promoted the growth of large hepatocarcinomas likely by a mechanism involving increased proliferation and the activation of cells expressing stemness markers. These results could be of interest to develop non-toxic AhR antagonists to restore liver structure and function after toxic injury or after surgical intervention. Lack of AhR could be considered a bad prognostic value in liver cancer

Methods

Results

Conclusion