The Expression of Glyceraldehyde-3-Phosphate Dehydrogenase Associated Cell Cycle (GACC) Genes Correlates with Cancer Stage and Poor Survival in Patients with Solid Tumors

Dunrui Wang,Daniel R Moothart,Xiaolan Qian,Douglas R Lowy,Jonathan A Coles

doi:10.1371/journal.pone.0061262

Dunrui Wang, Daniel R Moothart + Show 3 more

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https://doi.org/10.1371/journal.pone.0061262

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Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is often used as a stable housekeeping marker for constant gene expression. However, the transcriptional levels of GAPDH may be highly up-regulated in some cancers, including non-small cell lung cancers (NSCLC). Using a publically available microarray database, we identified a group of genes whose expression levels in some cancers are highly correlated with GAPDH up-regulation. The majority of the identified genes are cell cycle-dependent (GAPDH Associated Cell Cycle, or GACC). The up-regulation pattern of GAPDH positively associated genes in NSCLC is similar to that observed in cultured fibroblasts grown under conditions that induce anti-senescence. Data analysis demonstrated that up-regulated GAPDH levels are correlated with aberrant gene expression related to both glycolysis and gluconeogenesis pathways. Down-regulation of fructose-1,6-bisphosphatase (FBP1) in gluconeogenesis in conjunction with up-regulation of most glycolytic genes is closely related to high expression of GAPDH in the tumors. The data presented demonstrate that up-regulation of GAPDH positively associated genes is proportional to the malignant stage of various tumors and is associated with an unfavourable prognosis. Thus, this work suggests that GACC genes represent a potential new signature for cancer stage identification and disease prognosis.

Highlights

The gene encoding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is frequently used as a stable marker for constitutive gene expression, its expression is not always constant, especially in cancer
Preliminary analysis suggested the transcription of some cell cycle genes in the non-small cell lung cancer (NSCLC) dataset might correlate with the transcription of GAPDH
The study data were analyzed using the Affymetrix GeneChip Human Genome U133 plus2 or U133A Array formats, which are commonly used for gene expression detection

Summary

Introduction

The gene encoding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is frequently used as a stable marker for constitutive gene expression, its expression is not always constant, especially in cancer. In one study of non-small cell lung cancer (NSCLC), GAPDH was the least stable of the 6 ‘‘reference’’ genes examined [1]. This housekeeping glycolytic enzyme has been implicated in multiple functions and has been found to be over-expressed in certain cancers [2]. Recent studies aimed at evaluating this hypothesis have demonstrated that cancer cells have adapted their metabolism to facilitate the uptake and incorporation of nutrients into the biomass required to produce new cells [4]. As a key intermediate component of glycolysis, GAPDH could serve an important role in cancer cell development and tumor progression. In one possibly cancer-related scenario, GAPDH was found to be a prosurvival regulator of caspase-independent cell death (CICD) [10]

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