br Introduction Lung cancer is the
Introduction Lung cancer is the leading cause of cancer death worldwide and is one of the most refractory of solid tumors along with pancreatic cancer. Since 1975 there have been notable improvements in the 5-year survival rate of patients with lung cancer . This improvement in survival is thought to be the result of earlier diagnoses and more effective types of treatment. In Japanese cases of lung cancer surgery, the 5-year survival rate for surgical cases was 69.6% in 2004, but this rate is unsatisfactory even for patients who undergo complete curative surgery . Thus, novel biomarkers and therapeutic targets for non-small cell lung cancer (NSCLC) are urgently required. The metabolism of cancer cells has been reprogrammed to support their rapid proliferation . A number of studies have shown that many metabolic genes play an important role in cancer progression, and have potential utility as prognostic markers as well as therapeutic targets. Glycolysis and lipogenesis are essential metabolic processes in cancer cells. In the 1920s, Otto Warburg discovered that cancer cells, in contrast to normal cells, exhibit high levels of glycolysis even under aerobic conditions . It was later found that cancers derive most of their fatty acids from lipogenesis . Glycolysis is the biochemical process that breaks glucose down to pyruvate and generates adenosine triphosphate (ATP), which is the major source of energy in cancer cells . Moreover, the fatty AS601245 synthesized during lipogenesis is used as the major fuel for cell membrane production in rapidly proliferating cancer cells . Currently, there are at least five genes in the glycolytic and lipogenic pathways that are known to be directly involved in tumorigenesis and tumor progression, namely glucose transporter 1 (GLUT1), phosphoglucose isomerase (PGI), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) . In particular, GLUT1 facilitates increased transport of glucose into cancer cells to maintain an elevated rate of glycolysis under aerobic conditions, while ACLY is a cytosolic enzyme that converts citrate to acetyl-CoA for lipogenesis . Thus, GLUT1 and ACLY are thought to be critical enzymes in the first rate-limiting step of their respective metabolic pathways. Upregulation of both GLUT1 and ACLY has been shown in various types of tumors, including breast, colorectal, gastric cancer and hepatocellular carcinoma , , , . Notably, overexpression of both GLUT1 and ACLY is significantly associated with poor survival in patients with NSCLC , , , , , . Previous studies have reported that both GLUT1 and ACLY expression have potential utility as prognostic markers. Additionally, GLUT and ACLY activities are closely connected to each other, because ACLY functions as a crosslink between glycolysis and lipogenesis. However, few studies have examined both of these genes simultaneously. A previous study demonstrated that combined analysis of metabolic genes, including PGI, ACLY, ribonucleoside diphosphate reductase subunit M2 (RRM2) and thymidylate synthase (TYMS), could be of significant prognostic value in patients with breast carcinoma . However, there have been no similar studies of patients with NSCLC. Therefore, to investigate the prognostic impact of the levels of metabolic gene combinations in patients with NSCLC, we analyzed GLUT1 and ACLY expression in patients with NSCLC. This study provides evidence that the combination of GLUT1 and ACLY expression could be a more valuable prognostic marker than each gene expressed individually in patients with NSCLC.
Material and methods
Discussion The purpose of this study was to investigate the impact of the combined status of metabolic genes on cancer progression in NSCLC patients, and to determine if analysis of co-expression of these genes had better predictive value than analysis of individual gene expression. It has already been reported that a combination analysis of four metabolic genes is associated with poor outcome in patients with breast carcinoma, but a similar study has not yet been reported for patients with NSCLC . The present study is the first report to investigate the association of the combined status of metabolic genes with clinical outcome in NSCLC patients. Although this study was limited, being a preliminary and retrospective study, we showed using multivariate analysis that a double-positive status of GLUT1 and ACLY is an independent negative prognostic factor for node-negative patients with NSCLC.