Abstract
BackgroundAldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle. Recently, a new role of ALDOA in several cancers has been proposed. However, the underlying mechanism remains obscure and inconsistent. In this study, we tried to investigate ALDOA-associated (AA) genes using available microarray datasets to help elucidating the role of ALDOA in cancer.ResultsIn the dataset of patients with non-small-cell lung cancer (NSCLC, E-GEOD-19188), 3448 differentially expressed genes (DEGs) including ALDOA were identified, in which 710 AA genes were found to be positively associated with ALDOA. Then according to correlation coefficients between each pair of AA genes, ALDOA-associated gene co-expression network (GCN) was constructed including 182 nodes and 1619 edges. 11 clusters out of GCN were detected by ClusterOne plugin in Cytoscape, and only 3 of them have more than three nodes. These three clusters were functionally enriched. A great number of genes (43/79, 54.4%) in the biggest cluster (Cluster 1) primarily involved in biological process like cell cycle process (Pa = 6.76E-26), mitotic cell cycle (Pa = 4.09E-19), DNA repair (Pa = 1.13E-04), M phase of meiotic cell cycle (Pa = 0.006), positive regulation of ubiquitin-protein ligase activity during mitotic cell cycle (Pa = 0.014). AA genes with highest degree and betweenness were considered as hub genes of GCN, namely CDC20, MELK, PTTG1, CCNB2, CDC45, CCNB1, TK1 and PSMB2, which could distinguish cancer from normal controls with ALDOA. Their positive association with ALDOA remained after removing the effect of HK2 and PKM, the two rate limiting enzymes in glycolysis. Further, knocking down ALDOA blocked breast cancer cells in the G0/G1 phase under minimized glycolysis. All suggested that ALDOA might affect cell cycle progression independent of glycolysis. RT-qPCR detection confirmed the relationship of ALDOA with CDC45 and CCNB2 in breast tumors. High expression of the hub genes indicated poor outcome in NSCLC. ALDOA could improve their predictive power.ConclusionsALDOA could contribute to the progress of cancer, at least partially through its association with genes relevant to cell cycle independent of glycolysis. AA genes plus ALDOA represent a potential new signature for development and prognosis in several cancers.
Highlights
Aldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle
Linear models identified 3448 genes differently expressed between non-small cell lung cancer (NSCLC) tumors and normal lung tissues (|Fold Change (FC)| > 1.5 and Adjusted P values (Pa) < 0.05), which were regarded as differentially expressed genes (DEGs)
1200 DEGs with P < 0.05 were identified as AA genes, of which the expression of 710 genes was positively correlated with ALDOA expression, while 490 genes were negatively correlated with ALDOA
Summary
Aldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle. A new role of ALDOA has been proposed, given that ALDOA is highly expressed in a variety of malignant cancers, including human lung cancer [4], osteosarcoma [5], colorectal cancer [6], oral squamous cell carcinomas [7] and hepatocellular carcinomas [8]. It could serve as a diagnostic and prognostic marker. RNA interference of ALDOA has been shown to inhibit cell proliferation in Ras-transformed NIH-3 T3 cells, there was no report on the potential mechanism or associated genes relevant to the role of ALDOA played in cell proliferation [10]
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