Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

Abstract

Abstract. Elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported in different human malignancies. To understand its role in hepatitis B virus (HBV) infection-associated hepatocellular carcinoma (HCC), the expression of GAPDH was quantitatively measured in a cohort of 72 male HCC patients without preoperative treatment, all with evidence of chronic HBV infection. Using C-terminal banding protein 1 (CTBP1) or hypoxanthine phosphori bosyltransferase 1 (HPRT1) as reference genes, the level of GAPDH mRNA in tumor tissue was found to be significantly higher compared with that in paired non tumor tissues (P=0.0087 for CTBP1; P=0.0116 for HPRT1). Accordingly, compared with the non-tumor tissue, 37.5% (27/72) of patients' tumor tissues had a more than 2-fold increase of GAPDH expression. Furthermore, following knockdown GAPDH expression via siRNA transient transfection, HepG2 cells exhibited enhanced resistance to cytosine arabinoside (IC 50 , 308.28 µM vs. 67.68 µM in the control; P=0.01). Notably, higher GAPDH expression was significantly associated with lower liver fibrosis score (P= 0.0394) and a tendency towards higher survival rates for patients with HCC. To the best of our knowledge, the present study is the first study to report that the elevated expression levels of GAPDH in HCC tumor tissue may be relevant to an improved fibrosis score and survival probability in male patients with HBV infection; however, the underlying mechanism requires further investigation. IntroductionHepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality in males and the sixth leading cause in females worldwide (1). In addition, HCC is ranked as the second leading cause of cancer-related mortality in China (2). Over 50% of the annual HCC cases reported worldwide are diagnosed in the Chinese population (3), while hepatitis B virus (HBV) infection is responsible for 80% of all HCC causes in China (4). While a number of studies have revealed that HBV infection is the key pathogenic factor for the development of HCC, male gender and cirrhosis have also been found to be independent risk factors for the occurrence of HCC (5-7). However, few studies exist on patients presenting all these risk factors.Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was initially considered to be an essential glycolytic enzyme that is expressed in all prokaryotic and eukaryotic organisms. GADPH plays a major role in cellular metabolism, converting glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate (8). In addition, studies have demonstrated that GAPDH is involved in certain important physiological functions, including the transport of transfer RNA (9), translational control (10)

Defects in long‐chain 3‐hydroxy acyl‐CoA dehydrogenase lead to hepatocellular carcinoma: A novel etiology of hepatocellular carcinoma

“…GAPDH is an enzyme of Glycolysis and catalyzes the conversion of Glyceraldehyde 3‐P to 1,3‐biphosphoglycerate. Increased abundance of GAPDH, as observed in HT‐LCHAD liver, is also reported in renal cell carcinoma, lung, breast, prostate cancers, HBV and HCV‐associated HCC . Increased glucose metabolism, a prominent biochemical signature and metabolic phenotype of most solid tumors and long known in case of liver tumors, plays an important role in several biosynthetic processes facilitating uncontrolled growth.…”

“…Increased abundance of GAPDH, as observed in HT-LCHAD liver, is also reported in renal cell carcinoma, lung, breast, prostate cancers, HBV and HCV-associated HCC. 31 Increased glucose metabolism, a prominent biochemical signature and metabolic phenotype of most solid tumors and long known in case of liver tumors, plays an important role in several biosynthetic processes facilitating uncontrolled growth. Furthermore, a strong link between GAPDH upregulation and c-Jun, a proto-oncogene involved in liver tumorigenesis has been reported.…”