Hepatology

Biography

Biography: Amedeo Columbano

Abstract

Warburg metabolism is associated with cancer, but remains unclear whether it characterizes early phases of tumorigenesis. Here, we performed a metabolic characterization by assessing expression level, activity and modulation of several enzymes with key roles in glycolysis, pentose phosphate pathway (PPP) and oxidative phosphorylation. Preneoplastic hepatic lesions and hepatocellular carcinomas (HCC) were induced in rats by a single dose of diethylnitrosamine (DENA) followed by 2-acetylaminoaminofluorene (2-AAF) and partial hepatectomy. Expression of metabolic genes was also analysed in macrodissected preneoplastic nodules and HCC cells obtained by perfusion of HCC-bearing rats and in two different cohorts of human patients carrying HCC. A switch from OXPHOS to PPP was observed in very early preneoplastic lesions generated 10 weeks after DENA treatment. This metabolic reprogramming was observed only in the most aggressive preneoplastic lesions positive for CK-19. PPP induction shown by increased glucose 6-phosphate dehydrogenase (G6PD) was associated with inhibition of succinate dehydrogenase by the chaperone TRAP1 and increased expression and activity of citrate synthase. Activation of the NRF2/KEAP1 pathway and down-regulation of miR-1 accompanied the metabolic reprogramming in CK-19+ preneoplastic lesions. Accordingly, NRF2 silencing decreases G6PD and increases miR1 expression, consequently inhibiting PPP, while forced expression of miR1 downregulated G6PD expression in HCC cells. Finally, an inverse correlation between miR1 and its target gene G6PD was found in human HCCs. The results demonstrate that metabolic reprogramming takes place at early stages of hepatocarcinogenesis and is likely the consequence of the concomitant activation/increase of the NRF2-KEAP1 pathway and TRAP1.