The relevance of mitochondrial BAX re-distribution for apoptotic evasion in human hepatocellular carcinoma

Background:

Resistance to cell death is a hallmark of many cancers including hepatocellular carcinoma (HCC). The chronic inflammatory microenvironment within liver predisposes HCC development and progression. Herein, tumor predisposition to apoptosis is reflected by the dynamic distribution of the pro-apoptotic BCL-2 proteins BAX/BAK between cytosol and mitochondria. However, underlying molecular mechanisms that maintain this equilibrium during hepatocarcinogenesis remain elusive.

Methods:

We employed integrative functional and molecular analyses and revealed distinct tumor biology in a subgroup of HCC patients determined by a shift of mitochondrial Bax but not Bak pool to the cytosol during malignant transformation.

Results:

The HCC subgroup with predominant cytosolic BAX localization harbored selective protection from BAX activation and apoptotic cell death, respectively. Molecularly, this subgroup showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. In contrast, non-protected HCCs followed activation of classical oncogenic networks. Importantly, gene expression profiles of protected HCCs were enriched in poorly differentiated HCCs and showed a significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of protected cancer cells resulted in profound apoptosis induction of cells otherwise insensitive to a variety of cell stresses upon PARP inhibition.

Conclusion:

Together, our results confirm that predisposition to mitochondrial apoptosis impairs tumor biology in HCC and might identify a subgroup of HCC patients with a specific response pattern and activated DNA repair mechanisms.