Critical cholangiocarcinogenesis control by cryptochrome clock genes

Abstract

A coordinated network of molecular circadian clocks in individual cells generates 24-hour rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. Since divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis.

Male WT and Cry1^-/-Cry2^-/- mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST, ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology.

Five months after initiation of DEN treatment, we found that Cry1^-/-Cry2^-/- mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1^-/-Cry2^-/- mice as compared to WT mice (p= 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly 8-fold increase in the average number of cholangiocarcinomas in Cry1^-/-Cry2^-/- mice, as compared to WT mice.

The study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically-induced liver carcinogenesis. In addition, the pronounced shift towards cholangiocarcinoma in DEN exposed Cry1^-/-Cry2^-/- mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis. This article is protected by copyright. All rights reserved.

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