High Glucose Promotes Pancreatic Ductal Adenocarcinoma Gemcitabine Resistance and Invasion through Modulating ROS/MMP-3 Signaling Pathway

Pancreatic ductal adenocarcinoma (PDA) is often concomitant with diabetes mellitus, which mainly manifests as an increased blood glucose level. Previous studies revealed that diabetic status reduced the survival and blunted gemcitabine sensitivity in PDA patients. This study is aimed at analyzing the mechanism of elevated gemcitabine resistance and cancer invasion ability under high glucose environment. We selected 129 patients with 22 surgical resected samples from 2015 to 2021, who underwent pancreatic surgery in Huashan Hospital. The gene expression and clinical data of PDA were obtained from The Cancer Genome Atlas (TCGA) website and were analyzed by R software. Cell viability assays and flow cytometry were applied to detect gemcitabine sensitivity and apoptosis levels in pancreatic cancer cells. Wound healing and Transwell tests were used to analyze the invasion and metastasis of cancer cells. Streptozotocin (STZ) was used to establish a hyperglycemic mouse model for the in vivo study. In this study, diabetic PDA gemcitabine users showed reduced survival compared to euglycemic PDA gemcitabine users. Clinical samples and laboratory studies revealed that MMP-3 expression was associated with glucose concentration and diabetic status. Elevated MMP-3 expression was positively related to cancer invasion and gemcitabine resistance in PDA cells and gemcitabine resistant PDA cells. Blocking MMP-3 expression inhibited gemcitabine resistance and cancer progression in cellular and animal models. MMP-3 was closely related to the expression of RRM1, a gemcitabine metabolism-related gene. Reactive oxygen species (ROS) level increased under higher glucose concentrations and was mediated by NOX4. ROS determined the MMP-3 expression in pancreatic cancer cells. Inhibiting NOX4 expression effectively suppressed MMP-3 expression, gemcitabine resistance, and cancer invasion. In conclusion, a high glucose environment induces gemcitabine resistance and cancer invasion via ROS/MMP-3 signaling pathway. MMP-3 can be a potential novel target for suppressing gemcitabine resistance and invasion in PDA.