Dataset Information

BOK promotes chemical-induced hepatocarcinogenesis in mice.

ABSTRACT: BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver. Of note, induction of CHOP and the pro-apoptotic BH3-only proteins PUMA and BIM by DEN was strongly reduced in the absence of BOK. Accordingly, Bok -/- mice were significantly protected from DEN-induced acute hepatocellular apoptosis and associated inflammation. As a consequence, Bok -/- animals were partially protected against chemical-induced hepatocarcinogenesis showing fewer and, surprisingly, also smaller tumors than WT controls. Gene expression profiling revealed that downregulation of BOK results in upregulation of genes involved in cell cycle arrest. Bok -/- hepatocellular carcinoma (HCC) displayed higher expression levels of the cyclin kinase inhibitors p19INK4d and p21cip1. Accordingly, hepatocellular carcinoma in Bok -/- animals, BOK-deficient human HCC cell lines, as well as non-transformed cells, showed significantly less proliferation than BOK-proficient controls. We conclude that BOK is induced by DEN, contributes to DEN-induced hepatocellular apoptosis and resulting hepatocarcinogenesis. In line with its previously reported predominant localization at the endoplasmic reticulum, our findings support a role of BOK that links the cell cycle and cell death machineries upstream of mitochondrial damage.

SUBMITTER: Rabachini T

PROVIDER: S-EPMC5864194 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

BOK promotes chemical-induced hepatocarcinogenesis in mice.

Rabachini Tatiana T Fernandez-Marrero Yuniel Y Montani Matteo M Loforese Giulio G Sladky Valentina V He Zhaoyue Z Bachmann Daniel D Wicki Simone S Villunger Andreas A Stroka Deborah D Kaufmann Thomas T

Cell death and differentiation 20171211 4

BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK m ...[more]

PMID: 29229991

Similar Datasets

Project description:Activation of beta-catenin, the central effector of the canonical Wnt pathway and a recognized oncogene, has been implicated in hepatocellular carcinoma. We examined N-nitrosodiethylamine (DEN)-induced tumorigenesis in hepatic beta-catenin conditional knockout mice (beta-cat KO). Male beta-cat KO and age- and sex-matched littermate controls were given a single intraperitoneal DEN injection and followed for 6-12 months for hepatic tumors. Hepatic tumors were characterized for histology, proliferation, apoptosis, oxidative stress, and specific proteins by way of western blot, immunohistochemistry, and coprecipitation studies. For in vivo tumor intervention studies, specific inhibitors were administered intraperitoneally or through drinking water. Intriguingly, beta-cat KO mice showed a paradoxical increase in susceptibility to DEN-induced tumorigenesis. This accelerated tumorigenesis is due to increased injury and inflammation, unrestricted oxidative stress, fibrosis, and compensatory increase in hepatocyte proliferation secondary to platelet-derived growth factor receptor alpha (PDGFRalpha)/phosphoinositide 3-kinase (PIK3CA)/Akt activation and c-Myc overexpression. In vitro suppression of beta-catenin expression in hepatoma cells led to enhanced PDGFRalpha expression, which was abrogated in the presence of nuclear factor kappaB (NF-kappaB) inhibitor. Daily treatment of 6-month-old DEN-exposed beta-cat KO with PDGFRalpha inhibitor dramatically reduced tumor numbers and size. Inclusion of N-acetyl-L-cysteine, a known antioxidant and NF-kappaB inhibitor, in the drinking water led to complete abolition of tumorigenesis in DEN-exposed beta-cat KO.Loss of beta-catenin impairs the liver's ability to counteract DEN-induced oxidative stress and enhances tumorigenesis through PDGFRalpha/PIK3CA/Akt signaling. Blockade of PDGFRalpha or oxidative stress dramatically affects beta-catenin-deficient tumorigenesis. Also, hepatoma cells use PDGFRalpha/PIK3CA signaling as an escape mechanism following beta-catenin suppression, and their sequential suppression profoundly impedes tumor proliferation.

Dataset Information

BOK promotes chemical-induced hepatocarcinogenesis in mice.

Publications

BOK promotes chemical-induced hepatocarcinogenesis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets