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.

Targeting BCL-2 regulated apoptosis in cancer

“…More recently, in a chemical (DEN)-induced model of liver carcinogenesis, loss of BOK has been shown to protect against cancer. In this model, cancer can be promoted by death of hepatocytes, supporting compensatory proliferation with associated mutagenesis, in surrounding tissue that ultimately leads to live cancer [ 114 ]. Interestingly, deletion of BOK inhibited the ER-stress response and induction of pro-apoptotic BH3-only proteins BIM and PUMA, placing BOK's tumour promoting role upstream of MOMP [ 114 ].…”

“…In this model, cancer can be promoted by death of hepatocytes, supporting compensatory proliferation with associated mutagenesis, in surrounding tissue that ultimately leads to live cancer [ 114 ]. Interestingly, deletion of BOK inhibited the ER-stress response and induction of pro-apoptotic BH3-only proteins BIM and PUMA, placing BOK's tumour promoting role upstream of MOMP [ 114 ]. Secondly, BOK was also shown to have an additional growth-promoting effect, though the mechanisms underlying this remain unclear it would also be expected to be pro-tumourigenic [ 114 ].…”

“…Interestingly, deletion of BOK inhibited the ER-stress response and induction of pro-apoptotic BH3-only proteins BIM and PUMA, placing BOK's tumour promoting role upstream of MOMP [ 114 ]. Secondly, BOK was also shown to have an additional growth-promoting effect, though the mechanisms underlying this remain unclear it would also be expected to be pro-tumourigenic [ 114 ].…”

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

“…Several studies suggest that BOK exerts its anti-tumorigenic effects through non-apoptotic functions [82,83]. On the other hand, a pro-tumorigenic role for BOK is reported in hepatocellular carcinoma where deletion of BOK is infrequent [84].…”

Understanding the inflammation-cancer transformation in the development of primary liver cancer

“…This process helps promote the development and progression of liver cancer. The process involved many mechanisms such as oxidative stress, endoplasmic reticulum stress and mitochondrial damage, which will activate and promote the synthesis and secretion of tumor-related transcription factors and cytokines, resulting in DNA damage and further promoting tumorigenesis [15][16][17][18] .…”