Abstract
BackgroundSirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically.MethodsThe correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB).ResultsIHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis.ConclusionsDown-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.
Highlights
Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types
Immunohistochemical expression pattern of Sirt3 in paired tumoral and peritumoral tissues We found that the majorities of tumoral and peritumoral tissues showed diffuse cytoplasmic expression pattern of Sirt3 (Figure 1)
Peritumoral Sirt3 may serve as a protector of recurrence of hepatocellular carcinoma (HCC) through preventing the generation of reactive oxygen species (ROS). These results highlight the important role of remanent liver in recurrence and metastasis, and will be helpful in shaping postoperative strategy for the prevention of recurrence after hepatectomy. This present study indicated that both intratumoral and peritumoral Sirt3 expression were associated with prognosis in HCC
Summary
Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. Its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. Hepatocellular carcinoma (HCC), with rising incidence in the west, is the third leading cause of cancer-related death worldwide [1]. A member of the family, functions mainly as the primary mitochondrial deacetylase that modulates mitochondrial metabolic and oxidative stress regulatory pathways [9,13,14]. The proliferation-suppressor role of Sirt was confirmed in multiple cancer types, including breast cancer and colon cancer, both in vitro and in vivo [6,18]; it was reported that Sirt could inhibit HCC cell growth through reducing Mdm2mediated p53 degradation [19].
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