Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: Role of statins and metformin

Abstract

Hepatocellular carcinoma is the third leading cause of cancer-related deaths in the world. It is associated with an important mortality rate and the incidence is increasing. Patients showing metabolic syndrome seem to have higher incidence and mortality rates from hepatocellular carcinoma than healthy subjects, especially those with type 2 diabetes mellitus and obesity. Thus, metformin and statins, both to treat features of metabolic syndrome, have been proposed to decrease the risk of hepatocellular carcinoma. Otherwise, liver cancer is the result of a complex process which impairs several signaling cascades, such as RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Wnt/β-catenin signaling. Metformin (through 5'-adenosine monophosphate-activated protein kinase pathway activation) and statins (through 3-hydroxy-3-methylglutaryl coenzyme A inhibition) show anti-tumoral properties modifying several steps of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR and Wnt/β-catenin signaling cascades. On the other hand, metformin and statins have been found to reduce the risk of hepatocellular carcinoma up to 50% and 60%, respectively. Furthermore, both drugs have shown a dose-dependent protective effect. However, information about chemopreventive role of metformin and statins is mainly obtained of observational studies, which could not take into account some bias. In conclusion, given the rising of incidence of hepatocellular carcinoma and the important morbidity and mortality rates associated with this cancer, looking for chemopreventive strategies is an essential task. Randomized controlled trials are needed to determine the definite role of metformin and statins on the prevention of hepatocellular carcinoma.

Keywords: Hepatocellular carcinoma; Mammalian target of rapamycin; Metabolic syndrome; Metformin; Statin.

Figure 1

Pathogenic pathways of hepatocellular carcinoma and targets for metformin and statins. PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase; AMPK: Adenosine monophosphate-activated protein kinase; mTOR: Mammalian target of rapamycin; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular-signal-regulated kinase; GSK3-β: Glycogen synthase kinase 3 beta; EGF: Epidermal growth factor; VEGF: Vascular EGF; IGF: Insulin-growth factor; EGFR: EGF receptor; VEGFR: VEGF receptor; IGFR: IGF receptor.