BOK promotes chemical-induced hepatocarcinogenesis in mice

作者：Rabachini Tatiana; Fernandez Marrero Yuniel; Montani Matteo; Loforese Giulio; Sladky Valentina; He Zhaoyue; Bachmann Daniel; Wicki Simone; Villunger Andreas; Stroka Deborah; Kaufmann Thomas^*

来源：Cell Death and Differentiation, 2018, 25(4): 706-718.

DOI：10.1038/s41418-017-0008-0

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 p19(INK4d) and p21(cip1). 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.

• 出版日期2018-3