Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Acti-vating 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)/13-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/13-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/13-catenin 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/13-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/13-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 13-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/13-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of precancerous pancreatic lesions by activating the Wnt/13-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/13catenin signaling pathway.

Automated summary

Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/13-catenin signaling pathway, with related molecules being overexpressed in PDAC tissues/cells, and exacerbating the abnormal activation of 13-catenin.