G6PD activity, oxidative stress, and Alu methylation in HBV-related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading caused cancer death in worldwide. The effective diagnosis markers are needed because of the late diagnosis and low survival time. G6PD is the rate-limiting enzyme in pentose phosphate pathway (PPP) that elevated in several cancers including HCC. Alu element is a common repetitive sequence in human genome, that its methylation alteration has been reported in cancers. In this study, we aimed to investigate the level of blood G6PD activity, the expression of G6PD in HCC liver tissues, the level of Alu methylation in PBMCs and clinicopathological parameters of HCC patients. Blood G6PD activity was significantly increased in HCC patients (p<0.001) and correlated with HBV infection (p=0.013) and advanced stage (p=0.044) of HCC. The sensitivity and specificity of blood G6PD activity for HCC diagnosis were 57.47% and 61.54%, respectively. The presence of leukocytosis and activation of G6PD activity in PBMCs from cancer communication contribute the increase of blood G6PD activity. In the independent cohort of G6PD expression in HCC liver tissues, G6PD was elevated in cancerous area of HCC tissues, which correlated with HBV status, serum AFP, advanced stage, and recurrence. G6PD overexpression is an independent factor affecting short overall survival (OS) and progression free survival (PFS) time in HCC. In the part of epigenetics, Alu hypomethylation in whole blood samples and PBMCs of HCC patients was increased in HCC patients with HBV-related HCC and advanced stage. Furthermore, inhibition of G6PD via siRNA in HepG2 and HepG2. 2.2.15 reduced cancer proliferation, induced cell death, and increased 8-OHdG expression. In addition, G6PD knocked down induced Alu methylation change in HCC cells via oxidative stress. From this study, It pointed out that the increased expression of G6PD in liver cancer tissue and increased blood G6PD activity were risk factors for liver cancer progression. Therefore, understanding the association of G6PD, Alu methylation and oxidative stress might be a potential target for HCC prognosis and treatment in the future.