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)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by
activating the Wnt/β-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/βcatenin 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/β-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/β-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 β-catenin in PDAC and enhanced the
malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the
formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro.
Conclusion:
Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.