Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer

Background: Diabetes 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. Methods: HIF-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1 alpha 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-1 alpha. Conclusion: Our results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer. (c) 2018 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).