Gene Expression Meta-Analysis Identifies VDAC1 as a Predictor of Poor Outcome in Early Stage Non-Small Cell Lung Cancer

Abstract

BackgroundThe bioenergetic status of non-small cell lung cancer correlates with tumour aggressiveness. The voltage dependent anion channel type 1 (VDAC1) is a component of the mitochondrial permeability transition pore, regulates mitochondrial ATP/ADP exchange suggesting that its over-expression could be associated with energy dependent processes including increased proliferation and invasiveness. To test this hypothesis, we conducted an in vivo gene-expression meta-analysis of surgically resected non-small cell lung cancer (NSCLC) using 602 individual expression profiles, to examine the impact of VDAC1 on survival.Methodology/Principal FindingsHigh VDAC1 expression was associated with shorter overall survival with hazard ratio (HR) = 0.6639 (95% confidence interval (CI) 0.4528 to 0.9721), p = 0.035352 corresponding to 52 versus 101 months. VDAC1 predicted shorter time to recurrence and was shown to be an independent prognostic factor compared with histology, gender, age, nodal stage and tumour stage in a Cox multivariate analysis. Supervised analysis of all the datasets identified a 6-gene signature comprising HNRNPC, HSPA4, HSPA9, UBE2D2, CSNK1A1 and G3BP1 with overlapping functions involving regulation of protein turnover, RAS-RAF-MEK pathway and transcription. VDAC1 predicted survival in breast cancer and myeloma and an unsupervised analysis revealed enrichment of the VDAC1 signature in specific subsets.ConclusionsIn summary, gene expression analysis identifies VDAC1 gene expression as a predictor of poor outcome in NSCLC and other cancers and is associated with dysregulation of a conserved set of biological pathways, which may be causally associated with aggressive tumour behaviour.

Expression of a Truncated Active Form of VDAC1 in Lung Cancer Associates with Hypoxic Cell Survival and Correlates with Progression to Chemotherapy Resistance

“…Gene expression of VDAC1 has been reported to predict poor outcome in early-stage non-small cell lung cancer (37). In addition, VDAC1 was shown to be upregulated in prednisolone-sensitive acute lymphoblastic leukemia cells but not in resistant cells (38).…”

Voltage-Dependent Anion Channel 1 Interacts with Ribonucleoprotein Complexes To Enhance Infectious Bursal Disease Virus Polymerase Activity

“…Studies have shown that the expression of VDAC1 is much higher in tumor cells than in normal cells (29)(30)(31), and the increased expression of VDAC1 serves as an important factor in the process of mitochondrion-mediated apoptosis (19,(32)(33)(34)(35). Viruses are known to modulate apoptosis at the mitochondrial level via multiple strategies (36)(37)(38)(39)(40).…”

The proteomic 2D-DIGE approach reveals the protein voltage-dependent anion channel 2 as a potential therapeutic target in epithelial thyroid tumours

“…In 2011, Grills et al showed that overexpression of VDAC1 in tumours can predict a shorter time to recurrence of disease and shorter overall survival in patients (Grills et al, 2011). In thyroid tissue, this isoform was detected in benign tumours as well as in malignant lesions, showing a strong positivity in follicular thyroid carcinomas (Torres-Cabala et al, 2006).…”

“…Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / m c e interactions with enzymes able to favour glycolysis (Grills et al, 2011;Leanza et al, 2013;Maldonado et al, 2013). Several authors propose that these proteins have the capacity to act as a facultative regulator or effector of mitochondrial membrane permeabilization (MMP), depending on the initial cytotoxic event (Fiek et al, 1982;Linden and Karlsson, 1996;Schein et al, 1976;Shimizu et al, 1999;Shinohara et al, 2000).…”