Li Wei, Liu Han, Qian Weikun, Cheng Liang, Yan Bin, Han Liang, Xu Qinhong, Ma Qingyong, Ma Jiguang
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, China.
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Shandong 250012, China.
Comput Struct Biotechnol J. 2018 Oct 29;16:479-487. doi: 10.1016/j.csbj.2018.10.006. eCollection 2018.
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.
HIF-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.
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. 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 CoCl concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1α.
Our results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer.
糖尿病与胰腺癌密切相关。我们之前的研究表明，高血糖水平会促进胰腺癌的上皮-间质转化。在本研究中，我们评估了高血糖与缺氧肿瘤微环境之间的关系。
通过免疫组织化学评估临床胰腺癌组织中有无糖尿病时缺氧诱导因子-1α（HIF-1α）的表达。进行统计学分析以探讨HIF-1α表达与胰腺癌患者病理特征之间的关系。建立体内和体外模型，以检测高血糖环境是否会导致胰腺实质缺氧并促进胰腺癌。此外，我们还检测了HIF-1α小干扰RNA（siRNA）对高糖诱导的培养的BxPC-3细胞侵袭和迁移能力的影响。
我们的数据显示，与血糖正常组相比，患有糖尿病的胰腺癌患者HIF-1α表达水平更高，胆管侵犯更多，肿瘤体积更大。用链脲佐菌素（STZ）治疗的糖尿病裸鼠比对照小鼠表现出更大的肿瘤，并且更易发生肝转移。糖尿病小鼠胰腺的腺泡细胞显示内质网明显扩张，核间隙增加，并且在一些腺泡细胞中染色质靠近细胞膜。糖尿病原位异种移植组中Hypoxyprobe-1和HIF-1α的表达面积大于对照组。BxPC-3癌细胞系中HIF-1α的表达水平在高糖和氯化钴浓度作用下升高。HIF-1α特异性siRNA可抵消高糖诱导的侵袭能力、迁移能力和基质金属蛋白酶-9（MMP-9）表达。
我们的结果表明，高血糖与预后不良之间的关联可归因于胰腺癌中的微环境缺氧。
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