Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/s-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/s-catenin signaling pathway remains unclear. METHODS: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/scatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/s-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. RESULTS: Wnt/s-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of s-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/s-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/s-catenin signaling pathway in vivo and in vitro. CONCLUSION: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/s-catenin signaling pathway.