Abstract
BackgroundDiabetes mellitus and pancreatic cancer are intimately related. Our previous studies showed that high levels of blood glucose promote epithelial-mesenchymal transition of pancreatic cancer. In this study, we evaluated the relationship between hyperglycemia and hypoxic tumor microenvironments. MethodsHIF-1α expression was evaluated by immunohistochemistry in clinical pancreatic cancer tissues with or without diabetes mellitus. Statistcal analysis was performed to explore the relationship between HIF-1α expression and pathological features of patients with pancreatic cancer. In vivo and in vitro models was established to detect whether a hyperglycemia environment could cause hypoxia in the pancreatic parenchyma and promote pancreatic cancer. In addition, we also tested the effect of HIF-1α siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture. ResultOur data showed that pancreatic cancer patients with diabetes had a higher level of HIF-1α expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice. Acinar cells of the pancreas in diabetic mice showed an obvious expansion of the endoplasmic reticulum and increased nuclear gaps as well as chromatin close to the cellular membrane in some acinar cells. The expression area for Hypoxyprobe-1 and HIF-1α in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1α in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1α. ConclusionOur results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer.
Highlights
Diabetes mellitus and pancreatic cancer are intimately related
The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline (TBS) for 2 h and probed with hypoxia-inducible factor 1α (HIF-1α) and MMP-9 antibodies at 4 °C overnight
To explore the possible relationship between hyperglycemia and hypoxia, we examined the effects of high glucose concentrations and the expression of HIF-1α in pancreatic cancer cells
Summary
Our previous studies showed that high levels of blood glucose promote epithelial-mesenchymal transition of pancreatic cancer. We tested the effect of HIF-1α siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture. Result: Our data showed that pancreatic cancer patients with diabetes had a higher level of HIF-1α expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. The expression level of HIF-1α in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1α. Our previous studies found that high glucose levels could promote pancreatic cancer proliferation and invasion as well as epithelial-mesenchymal transition (EMT) and metastasis [7,8]. Recent studies have proven that hyperglycemia can induce cellular hypoxia and generate mitochondrial reactive oxygen species [9]
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