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

Author(s):

Huiming Chen, Junfeng Zhao, Ningning Jiang, Zheng Wang* and Chang Liu*   Pages 2592 - 2602 ( 11 )

Abstract:

<P>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)/&#946;-- catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/&#946;-catenin signaling pathway remains unclear. </P><P> Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/&#946;-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/&#946;-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. </P><P> Results: Wnt/&#946;-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 &#946;-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/&#946;-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of precancerous pancreatic lesions by activating the Wnt/&#946;-catenin signaling pathway in vivo and in vitro. </P><P> Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/&#946;- catenin signaling pathway.</P>

Keywords:

Pancreatic ductal adenocarcinoma, hyperglycemia, Wnt/&#946;-catenin, signaling pathway, tumor initiation and progression, pancreatic cancer.

Affiliation:

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Department of General Surgery, Shaanxi Provincial Rehabilitation Hospital, Xi'an 710065, Shaanxi, Department of General Surgery, Shaanxi Provincial Rehabilitation Hospital, Xi'an 710065, Shaanxi, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061

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