Abstract
A concurrent increase in the prevalence of hepatocellular carcinoma (HCC) with that of type 2 diabetes (T2D) and obesity has been reported in the absence of hepatitis B virus surface antigen-negative/hepatitis C virus antibody-negative HCC (NBNC-HCC). However, the prognostic relevance of this association remains unclear. Promoter methylation (PM) of the dihydropyrimidinase-like 3 gene (DPYSL3) has been implicated in virus-related HCC. However, it remains unclear whether T2D influences PM in NBNC-HCC. We determined the influence of T2D on clinicopathological profile and PM of DPYSL3 and CDK2NA in patients with NBNC-HCC who were divided into two groups: non-diabetes (non-DM; n = 46) and diabetes (DM; n = 47). DM was associated with a higher Union for International Cancer Control grade, marginal vascular invasion and tumour cell proliferation irrespective of the duration of T2D as well as higher rates of PM of DPYSL3 than non-DM; however, PM of CDK2NA was similar between both groups. PM of DPYSL3 reduced its expression which inversely correlated with reduced patient survival. In conclusion, T2D is associated with poor prognosis of NBNC-HCC in which a high frequency of PM of DPYSL3 may play a pivotal role in its pathogenesis.
Highlights
A concurrent increase in the prevalence of hepatocellular carcinoma (HCC) with that of type 2 diabetes (T2D) and obesity has been reported in the absence of hepatitis B virus surface antigen-negative/ hepatitis C virus antibody-negative HCC (NBNC-HCC)
We previously demonstrated that enhanced Promoter methylation (PM) of CDH1 in long-term T2D is associated with poor prognosis of pancreatic ductal cancer (PDC)[26]
To the best of our knowledge, for the first time, we demonstrated that T2D had a negative impact on disease-specific survival (DSS) and overall survival (OS) of patients with NBNC-HCC
Summary
A concurrent increase in the prevalence of hepatocellular carcinoma (HCC) with that of type 2 diabetes (T2D) and obesity has been reported in the absence of hepatitis B virus surface antigen-negative/ hepatitis C virus antibody-negative HCC (NBNC-HCC). Promoter methylation (PM) of the dihydropyrimidinase-like 3 gene (DPYSL3) has been implicated in virus-related HCC. It remains unclear whether T2D influences PM in NBNC-HCC. Cancer is the leading cause of death in patients with T2D, with HCC being the most prevalent[5]. The PM status of tumour suppressor genes can be related to the prognosis of HCC17,18 One such tumour suppressor gene is dihydropyrimidinase-like 3 (DPYSL3), a cell adhesion molecule expressed in the heart, brain and liver[19]. In HCC, the reduced expression level of DPYSL3 through PM is inversely correlated with the expression of vascular endothelial growth factor (VEGF) and focal adhesion kinase (FAK), resulting in poor prognosis of HCC23
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