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

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.

Glyceraldehyde-3-phosphate dehydrogenase gene over expression correlates with poor prognosis in non small cell lung cancer patients

“…Our results for GAPDH also agree with the findings of a very recent paper from Wang et al [34] in which the authors show the prognostic value of some genes correlated with GAPDH (GACC genes) together with GAPDH itself; Sh2008 was used as verification dataset. Authors don't show the prognostic performance of GAPDH alone; however, our results, confirmed on a large number of public datasets including Sh2008, suggest that large part of the prognostic performances shown in Sh2008 have to be attributed to GAPDH alone.…”

“…Actually this substitution was based on the strict metabolic relation between the two catalytic proteins – however the high correlation of the two genes was verified in the other datasets, and is confirmed by other authors too [34]. So, Ro2009 results for TPI1 , very similar to GAPDH results in the other datasets, can further support that the prognostic capabilities of GAPDH in NSCLC reflect the role of the corresponding enzyme in glucose metabolism.…”

Normalizing to GADPH jeopardises correct quantification of gene expression in ovarian tumours – IPO8 and RPL4 are reliable reference genes

“…These observations are in line with previous studies on other tissue types that have discouraged use of GADPH and HPRT1 as RGs for clinical lung specimens [16] and renal cell cancer [24]. Most recently, a microarray study identified a group of genes highly correlated to GADPH up-regulation in various solid tumours, which were and proportionally associated with advanced stages [30]. Previous reports on GADPH in ovarian tissue have either pointed out higher expression in malignant than in benign tumours and normal tissue [6], or not meeting the GeNorm stability criteria [4].…”

Identification of reference genes for qRT-PCR in human lung squamous-cell carcinoma by RNA-Seq

“…However, tumor cells show various metabolic anomalies, in which the best known are the typical high rate of glycolysis and lactate production termed 'Warburg effect' [29]. How tumor cells establish this altered metabolic phenotype is not entirely clear, but here our RNA-Seq results showed that the expression levels of many enzymes involving in glucose metabolism's expression elevated many folds, such as GAPDH, PGK1, hexokinase 2 (HK2), the M2 type of pyruvate kinase (PKM2), and lactate dehydrogenase (LDH), echoed lots of previous research [29][30][31][32][33][34][35]. So our results indicated that GAPDH is not entirely suitable as the reference gene of qRT-PCR in lung squamous-cell carcinoma or even other kinds of cancers.…”