Knockout of Vdac1 activates the HIF signaling pathway and induces tumor development in vivo by promoting vascular remodeling and inflammation

ABSTRACT: Mitochondria are subcellular organelles that are more than just the powerhouse of cells, they also dictate if a cell dies or survives. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) has been shown to play a crucial role in metabolism and apoptosis, however its involvement in ischemic pathologies and cancer is not clear. Transcriptome analysis of Vdac1-/- mouse embryonic fibroblasts (MEF) highlighted cancer and inflammation as top diesases but also activation of the HIF-1 signaling pathway in normoxia. HIF-1α protein was stable due to ROS accumulation that decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia increased activation of ERK in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of ROS, thereby allowing Vdac1-/- MEF to proliferate better than wild-type MEF. Xenografts of RAS-transformed Vdac1-/- MEF in mice showed stabilization of both HIF-1α and HIF-2α which led to blood vessel destabilization and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was strongly decreased. Consequently RAS-transformed Vdac1-/- MEF tumors grew faster than wild-type MEF tumors. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases. Profiling of VDAC1-/- and wild-type (Wt) Mouse Embryonic Fibroblasts (MEFs) was performed using whole genome mouse microarrays. in normoxic or hypoxic conditions. MEF (Wt and Vdac1-/-) were incubated in normoxia (Nx, ie: 20% O2) or hypoxia (Hx, ie: 1% O2) for 72h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment with 2 biological replicates (marked 1 or 2) of the 4 experimental conditions. One condition (MEF WT Nx2) has been removed from the statistical analysis after microarray quality check due to high background. Total of 7 samples.

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Lebrigand 

PROVIDER: E-GEOD-63247 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress