Eguated MDM2 to prevent p53 degradation, which subsequently inhibited HCC cell growth [19]. In our study, SIRT3 was dramatically decreased in HCC cell lines and more than 200 HCC Eliglustat site tissue samples, at both mRNA and protein levels. Further data demonstrated that poorly-differentiated tumors expressed lessSIRT3 than well-differentiated tumors in most of HCC cases. Moreover, low SIRT3 expression was positively significantly correlated to advanced clinical stage, high serum AFP, multiple tumor numbers and higher relapse rate. Collectively, these data indicated loss of SIRT3 was coincident with tumor progression, which suggests SIRT3 as a tumor suppressor in HCC. However, the mechanistic nature of SIRT3 in inhibiting HCC progression remains poorly unknown, and it therefore deserts a challenge for future investigation.SIRT3 as a Prognostic Biomarker in HCCTable 3. Cox multivariate analyses of prognostic factors on overall survival.Variable Tumor multiplicity Tumor size AFP Differentiation Vascular invasion Stage Relapse SIRTb 0.141 0.116 0.750 20.020 0.519 0.954 0.807 20.SE 0.266 0.213 0.229 0.197 0.219 0.344 0.219 0.Hazard ratio (95 CI) 1.152 (0.683?.942) 1.124 (0.740?.706) 2.117 (1.352?.316) 0.981 (0.667?.442) 1.680 (1.093?.582) 2.596 (1.322?.100) 2.241 (1.459?.443) 0.555 (0.344?.897)P value0.596 0.585 0.001 0.921 0.018 0.006 0.000 0.worse prognosis. Strikingly, low SIRT3 expression could also predict poor overall survival of HCC patients with tumor size (,5 cm), grade (I-II), or stage (I-II). This suggested that decrease of SIRT3 in HCC could be of clinical significance for predicting outcome of surgical treatment in a MedChemExpress CB 5083 subset of HCC patients. In summary, our study provided vigorous evidence that low SIRT3 expression was frequently present in HCC, particularly in those poor-differentiated cases. Decrease of SIRT3 in HCC was significantly correlated with clinical stage, serum AFP level, tumor differentiation and tumor multiplicity, indicating that SIRT3 might be involved in HCC progression. Importantly, although little information of SIRT3 in hepatocarcinogenesis is available, our study suggests that low expression of SIRT3, as detected by IHC, may be useful for predicting the postoperative survival of HCC patients.b, Regression coefficient; SE, standard error; CI, confidence interval; AFP, alphafetoprotein. doi:10.1371/journal.pone.0051703.tSupporting InformationFigure S1 Percentages of high SIRT3 expressions in noncancerous tissue adjacent to HCC tissue were indicated by histogram. (TIF) Figure S2 Relation of SIRT3 expression with recurrence-free survival in pathological HCC subgroups. Survival analysis was performed in subgroups according to the factors that are attributed to worse outcome of HCC patients, using Kaplan-Meier survival analysis (log-rank test). (TIF) Figure S3 Survival analysis of SIRT3 expression in HCCLow SIRT3 expression has been identified as a poor independent prognostic factor for both overall survival and recurrence-free survival in postsurgical HCC patients in this study. There is no previous study reporting the association between SIRT3 expression and prognosis in cancer. However, high SIRT1 expression was reported to connect to poor survival in diffuse large B-cell lymphoma [40], gastric carcinoma [41], and breast cancer [42]. Furthermore, downregulation of SIRT1 in HCC resulted in abrogation of cell proliferation and enhanced sensitivity to doxorubicin treatment by induction of senescence or apoptosis [43,44]. The f.Eguated MDM2 to prevent p53 degradation, which subsequently inhibited HCC cell growth [19]. In our study, SIRT3 was dramatically decreased in HCC cell lines and more than 200 HCC tissue samples, at both mRNA and protein levels. Further data demonstrated that poorly-differentiated tumors expressed lessSIRT3 than well-differentiated tumors in most of HCC cases. Moreover, low SIRT3 expression was positively significantly correlated to advanced clinical stage, high serum AFP, multiple tumor numbers and higher relapse rate. Collectively, these data indicated loss of SIRT3 was coincident with tumor progression, which suggests SIRT3 as a tumor suppressor in HCC. However, the mechanistic nature of SIRT3 in inhibiting HCC progression remains poorly unknown, and it therefore deserts a challenge for future investigation.SIRT3 as a Prognostic Biomarker in HCCTable 3. Cox multivariate analyses of prognostic factors on overall survival.Variable Tumor multiplicity Tumor size AFP Differentiation Vascular invasion Stage Relapse SIRTb 0.141 0.116 0.750 20.020 0.519 0.954 0.807 20.SE 0.266 0.213 0.229 0.197 0.219 0.344 0.219 0.Hazard ratio (95 CI) 1.152 (0.683?.942) 1.124 (0.740?.706) 2.117 (1.352?.316) 0.981 (0.667?.442) 1.680 (1.093?.582) 2.596 (1.322?.100) 2.241 (1.459?.443) 0.555 (0.344?.897)P value0.596 0.585 0.001 0.921 0.018 0.006 0.000 0.worse prognosis. Strikingly, low SIRT3 expression could also predict poor overall survival of HCC patients with tumor size (,5 cm), grade (I-II), or stage (I-II). This suggested that decrease of SIRT3 in HCC could be of clinical significance for predicting outcome of surgical treatment in a subset of HCC patients. In summary, our study provided vigorous evidence that low SIRT3 expression was frequently present in HCC, particularly in those poor-differentiated cases. Decrease of SIRT3 in HCC was significantly correlated with clinical stage, serum AFP level, tumor differentiation and tumor multiplicity, indicating that SIRT3 might be involved in HCC progression. Importantly, although little information of SIRT3 in hepatocarcinogenesis is available, our study suggests that low expression of SIRT3, as detected by IHC, may be useful for predicting the postoperative survival of HCC patients.b, Regression coefficient; SE, standard error; CI, confidence interval; AFP, alphafetoprotein. doi:10.1371/journal.pone.0051703.tSupporting InformationFigure S1 Percentages of high SIRT3 expressions in noncancerous tissue adjacent to HCC tissue were indicated by histogram. (TIF) Figure S2 Relation of SIRT3 expression with recurrence-free survival in pathological HCC subgroups. Survival analysis was performed in subgroups according to the factors that are attributed to worse outcome of HCC patients, using Kaplan-Meier survival analysis (log-rank test). (TIF) Figure S3 Survival analysis of SIRT3 expression in HCCLow SIRT3 expression has been identified as a poor independent prognostic factor for both overall survival and recurrence-free survival in postsurgical HCC patients in this study. There is no previous study reporting the association between SIRT3 expression and prognosis in cancer. However, high SIRT1 expression was reported to connect to poor survival in diffuse large B-cell lymphoma [40], gastric carcinoma [41], and breast cancer [42]. Furthermore, downregulation of SIRT1 in HCC resulted in abrogation of cell proliferation and enhanced sensitivity to doxorubicin treatment by induction of senescence or apoptosis [43,44]. The f.
