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Glycogen synthase kinase-3? is associated with the prognosis of hepatocellular carcinoma and may mediate the influence of type 2 diabetes mellitus on hepatocellular carcinoma.

ABSTRACT: BACKGROUND: Although many studies have shown glycogen synthase kinase-3? (GSK-3?) was associated with type 2 diabetes mellitus (T2DM) and implicated with a wide range of cancers, the role of GSK-3? in hepatocellular carcinoma(HCC) and the correlation among GSK-3?, T2DM and HCC remains unclear. Our objectives were to identify the effect of p-Ser9-GSK-3? on the prognosis of patients with HCC and to learn more about the interaction among T2DM, GSK-3? and the prognosis of HCC. METHODS: Firstly we used reverse transcriptase-PCR(RT-PCR) and western blotting to determine the expression levels of GSK-3? and p-Ser9-GSK-3? in human HCC samples. We then used immunohistochemical staining to evaluate the expression pattern of p-Ser9-GSK-3? in 178 patients with HCC after curative partial hepatectomy. Finally we statistically analyzed the association of p-Ser9-GSK-3? and T2DM with the prognosis of patients with HCC. RESULTS: P-Ser9-GSK-3? was over-expressed in tumor tissues compared with their normal counterparts. Correlation and regression analysis indicated that the over-expression of p-Ser9-GSK-3? was significantly associated with T2DM, and the correlation coefficient was 0.259 (P?=?0.001). Multivariate analysis showed that the over-expression of p-Ser9-GSK-3?(P<0.001) and T2DM(P?=?0.008) were independently associated with poor prognosis of HCC, respectively. Further analysis demonstrated that these two variables are closely related with each other. CONCLUSION: The over-expression of p-Ser9-GSK-3? and T2DM are strongly correlated with worse surgical outcome of HCC. P-Ser9-GSK-3? may play a significant role in mediating the influence of T2DM on the prognosis of HCC.

SUBMITTER: Qiao G

PROVIDER: S-EPMC4144855 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase-3β is associated with the prognosis of hepatocellular carcinoma and may mediate the influence of type 2 diabetes mellitus on hepatocellular carcinoma.

Qiao Guoliang G Le Yuan Y Li Jun J Wang Lianghuan L Shen Feng F

PloS one 20140826 8

<h4>Background</h4>Although many studies have shown glycogen synthase kinase-3β (GSK-3β) was associated with type 2 diabetes mellitus (T2DM) and implicated with a wide range of cancers, the role of GSK-3β in hepatocellular carcinoma(HCC) and the correlation among GSK-3β, T2DM and HCC remains unclear. Our objectives were to identify the effect of p-Ser9-GSK-3β on the prognosis of patients with HCC and to learn more about the interaction among T2DM, GSK-3β and the prognosis of HCC.<h4>Methods</h4> ...[more]

PMID: 25157753

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Project description:BackgroundPrevious studies suggested that diabetes mellitus was associated with cancer risk and prognosis, but studies investigating the relationship between diabetes mellitus and survival in patients with hepatocellular carcinoma (HCC) reported inconsistent findings. To derive a more precise estimate of the prognostic role of diabetes mellitus in HCC, we systematically reviewed published studies and carried out a meta-analysis.MethodsEligible articles were identified in electronic databases from their inception through September 16, 2013. To evaluate the correlation between diabetes mellitus and prognosis in HCC, the pooled hazard ratios (HR) and their 95% confidence intervals (95% CI) for poorer overall and disease-free survivals were calculated by standard meta-analysis techniques with fixed-effects or random-effects models.Results21 studies with a total of 9,767 HCC patients stratifying overall survival and/or disease-free survival in HCC patients by diabetes mellitus status were eligible for meta-analysis. 20 studies with a total of 9,727 HCC cases investigated the overall survival, and 10 studies with a total of 2,412 HCC patients investigated the disease-free survival. The pooled HRs for overall survival and disease-free survival were 1.46 (95% CI, 1.29 to 1.66; P<0.001) and 1.57 (95% CI, 1.21 to 2.05; P = 0.001), respectively. The adjusted HRs for overall survival and disease-free survival were 1.55 (95% CI, 1.27 to 1.91; P<0.001) and 2.15 (95% CI, 1.75 to 2.63; P<0.001), respectively. In addition, for patients receiving hepatic resection, diabetes mellitus was associated with both poorer overall survival and poorer disease-free survival, and for patients receiving non-surgical treatment or patients receiving radiofrequency ablation, diabetes mellitus was associated with poorer overall survival. There was no evidence for publication bias.ConclusionDiabetes mellitus is independently associated with both poorer overall survival and poorer disease-free survival in HCC patients.

Project description:The impact of pre-existing diabetes mellitus (DM) on hepatocellular carcinoma (HCC) occurrence and prognosis is complex and unclear. The aim of this meta-analysis is to evaluate the association between pre-existing diabetes mellitus and hepatocellular carcinoma occurrence and prognosis.We searched PubMed, Embase and the Cochrane Library from their inception to January, 2011 for prospective epidemiological studies assessing the effect of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence, mortality outcomes, cancer recurrence, and treatment-related complications. Study-specific risk estimates were combined by using fixed effect or random effect models.The database search generated a total of 28 prospective studies that met the inclusion criteria. Among these studies, 14 reported the risk of HCC incidence and 6 studies reported risk of HCC specific mortality. Six studies provided a total of 8 results for all-cause mortality in HCC patients. Four studies documented HCC recurrence risks and 2 studies reported risks for hepatic decomposition occurrence in HCC patients. Meta-analysis indicated that pre-existing diabetes mellitus (DM) was significantly associated with increased risk of HCC incidence [meta-relative risk (RR)?=?1.87, 95% confidence interval (CI): 1.15-2.27] and HCC-specific mortality (meta-RR?=?1.88, 95%CI: 1.39-2.55) compared with their non-DM counterparts. HCC patients with pre-existing DM had a 38% increased (95% CI: 1.13-1.48) risk of death from all-causes and 91% increased (95%CI: 1.41-2.57) risk of hepatic decomposition occurrence compared to those without DM. In DM patients, the meta-RR for HCC recurrence-free survival was 1.93(95%CI: 1.12-3.33) compared with non-diabetic patients.The findings from the current meta-analysis suggest that DM may be both associated with elevated risks of both HCC incidence and mortality. Furthermore, HCC patients with pre-existing diabetes have a poorer prognosis relative to their non-diabetic counterparts.

Project description:Despite treatment with agents that enhance beta-cell function and insulin action, reduction in beta-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3beta (Gsk-3beta). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3beta to regulation of beta-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/-) exhibit insulin resistance and a doubling of beta-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3beta (Gsk-3beta+/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced beta-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2-/-), like the Ir+/- mice, are insulin resistant, but develop profound beta-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3beta activity associated with a marked reduction of beta-cell proliferation and increased apoptosis. Irs2-/- mice crossed with Gsk-3beta+/- mice preserved beta-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2-/- mice had increased cyclin-dependent kinase inhibitor p27(kip1) that was limiting for beta-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of beta-cell mass in Gsk-3beta+/- Irs2-/- mice was accompanied by suppressed p27(kip1) levels and increased Pdx1 levels. To separate peripheral versus beta-cell-specific effects of reduction of Gsk3beta activity on preservation of beta-cell mass, mice homozygous for a floxed Gsk-3beta allele (Gsk-3(F/F)) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce beta-cell-specific knockout of Gsk-3beta (betaGsk-3beta-/-). Like Gsk-3beta+/- mice, betaGsk-3beta-/- mice also prevented the diabetes of the Irs2-/- mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within beta-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of beta-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve beta-cells and prevent diabetes onset.

Dataset Information

Glycogen synthase kinase-3? is associated with the prognosis of hepatocellular carcinoma and may mediate the influence of type 2 diabetes mellitus on hepatocellular carcinoma.

Publications

Glycogen synthase kinase-3β is associated with the prognosis of hepatocellular carcinoma and may mediate the influence of type 2 diabetes mellitus on hepatocellular carcinoma.

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