Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels

Abstract

Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, a main feature of diabetes mellitus, and uncovered its effect on precancerous pancreatic intraepithelial neoplasia (PanIN) progression. In vivo induction of hyperglycemia with 100 mg/kg streptozotocin in Kras LSL G12D Pdx1Cre (KP) mice promoted the PanIN formation and progression. Preconditioning with a high-or low-glucose medium for 28 days showed that a high-glucose environment increased cell viability and sphere formation in PANC-1, a Kras-mutant human pancreatic ductal adenocarcinoma cell line, and mPKC1, a Krasmutant murine pancreatic cancer cell line. In contrast, no changes were observed in BxPC3, a Kras-wild-type human pancreatic cancer cell line. Orthotopic injection of mPKC1 into the pancreatic tails of BL6/J mice showed that cells maintained in high-glucose medium grew into larger tumors than did those maintained in low-glucose medium. Hyperglycemia strengthened the STAT3 phosphorylation, which was accompanied by elevated MYC expression in Kras-mutant cells. Immunohistochemistry showed stronger phosphorylated STAT3 (pSTAT3) and MYC staining in PanINs from diabetic KP mice than in those from euglycemic counterparts. STAT3 inhibition with 1 μM STAT3 inhibitor STATTIC in Krasmutant pancreatic cell lines blocked the cell viability-and sphere formation-enhancing effects of the hyperglycemic environment and reversed the elevated pSTAT3 and MYC expression. MYC knockdown did not affect cell viability but did reduce sphere formation. No decrease in pSTAT3 expression was observed upon siMYC treatment. In conclusion, hyperglycemia, on a Kras-mutant background, aggravates the PanIN progression, which is accompanied by elevated pSTAT3 and MYC expression.

Histological and transcriptional characterization of the pancreatic acinar tissue in type 1 diabetes

“… 33 34 Diabetes and hyperglycemia have been linked to an increased risk of developing pancreatic cancer. In a recent study by Sato et al, 35 a link is shown between hyperglycemia, the activation of MYC through STAT3, and the development of pancreatic cancer. 36 Similarly, estrogen receptor-related pathways have been linked to an increased risk of developing pancreatic cancer.…”

Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database

“…Poor glycaemic control may itself be an early symptom of (undetected) pancreatic cancer. 24 , 26 In such cases, glucose-lowering drugs may be prescribed and the resulting non-causal association is called protopathic bias (also referred to as reverse causation or unmeasured confounding by undiagnosed disease). 27 The issue is closely connected with a latency time as there needs to be a period of time between onset and diagnosis of disease for protopathic bias to be possible.…”

“…HbA1c is a measure of poor glycaemic control that is typically used to monitor treatment response in T2DM. Poor glycaemic control is known to be associated with pancreatic cancer [23][24][25] such that not accounting for it may lead to confounding by indication. Poor glycaemic control may itself be an early symptom of (undetected) pancreatic cancer.…”

Type 2 Diabetes Mellitus Intersects With Pancreatic Cancer Diagnosis and Development

“…One possible mechanism is the activation of the transforming growth factor-b1 (TGF-b1) pathway by glucose, which results in a decrease in the level of E-cadherin in pancreatic ductal cells and a significant mesenchymal phenotype that promotes tumor growth and metastasis (17). Hyperglycemia may also increase genetic instability and lead to KRAS mutations by activating O-GlcN acetylation and nucleotide deficiency (17,18). Finally, the mTOR pathway controls protein synthesis and autophagy, and its deregulation is associated with diabetes and PC (19)(20)(21)(22)(23).…”