Diabetes mellitus impacts on expression of DNA mismatch repair protein PMS2 and tumor microenvironment in pancreatic ductal adenocarcinoma

Abstract

ABSTRACT Aims/Introduction The mismatch repair (MMR) protein recognizes DNA replication errors and plays an important role in tumorigenesis, including pancreatic ductal adenocarcinoma (PDAC). Although PMS2, a MMR protein, is degraded under oxidative stress, the effects of diabetes are still unclear. Herein, we focused on whether diabetes affected MMR protein expression in PDAC. Materials and Methods Tissues from 61 surgically resected PDAC subjects were clinicopathologically analyzed. Immunohistochemical analysis was performed for MMR protein expression, oxidative stress, and immune cell infiltration. The change of MMR protein expression was assessed in PDAC cell lines under stimulation with 25 mM glucose and 500 μM palmitic acid. Survival curves were analyzed by the Kaplan–Meier method with the log‐rank test. Results Diabetes complicated with dyslipidemia significantly decreased the expression of PMS2 in PDAC tissues with an inverse correlation with the degree of oxidative stress. Palmitic acid combined with high glucose induced degradation of PMS2 protein, enhancing oxidative stress in vitro. CD8+ T‐cell infiltration was associated with a short duration of type 2 diabetes (≤4 years) and a low expression of PMS2 in PDAC tissues, while CD163+ tumor‐associated macrophage infiltration was increased with a long duration of diabetes (>4 years). A short duration of diabetes exhibited a better prognosis than nondiabetic subjects with PDAC (P < 0.05), while a long duration of diabetes had a worse prognosis (P < 0.05). Conclusions The different phases of diabetes have a major impact on PDAC by altering PMS2 expression and the tumor immune microenvironment, which can be targeted by an immune checkpoint inhibitor.

Keywords

• PMS2
• Diabetes mellitus
• Pancreatic ductal adenocarcinoma