Role of SIRT-3, p-mTOR and HIF-1α in hepatocellular carcinoma patients affected by metabolic dysfunctions and in chronic treatment with metformin

Serena De Matteis, Emanuela Scarpi, Anna Maria Granato, Umberto Vespasiani-Gentilucci, Giuliano La Barba, Francesco Giuseppe Foschi, Erika Bandini, Martina Ghetti, Giorgia Marisi, Paola Cravero, Laura Gramantieri, Alessandro Cucchetti, Giorgio Ercolani, Daniele Santini, Giovanni Luca Frassineti, Luca Faloppi, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

Research output: Contribution to journalArticlepeer-review


The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin-(SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor-(HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1α expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1α as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC.

Original languageEnglish
Article number1503
JournalInternational Journal of Molecular Sciences
Issue number6
Publication statusPublished - Mar 2 2019


  • Diabetes
  • Metabolic syndrome
  • Metformin
  • Non-alcoholic steatohepatitis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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