Zhang Dapeng, Cui Lihua, Li Shu Shun, Wang Feng
Principal Investigator Unit, Tianjin Institute of Integrative Medicines for Acute Abdominal Diseases, Nankai Hospital, Tianjin 300100, P.R. China.
Department of Clinical Immunology, Karolinska University Huddinge Hospital, Huddinge SE-14186, Sweden.
Oncol Lett. 2015 Sep;10(3):1545-1550. doi: 10.3892/ol.2015.3384. Epub 2015 Jun 17.
The aim of the present study was to investigate whether interstitial insulin and cancer-induced hypoxia-inducible factor-1 (HIF-1) cooperate in pancreatic cancer cells. A population of 45 nude mice were divided into one intact control group and six pancreatic tumor-carrier groups. Pancreatic tumors were generated using HIF-1-positive wild-type MiaPaCa2 (wt-MiaPaCa2) pancreatic cancer cells in three groups of carriers and MiaPaCa2 cells transfected with small interfering RNA against HIF-1α (si-MiaPaCa2 cells) in the other three carrier groups. To vary the intrapancreatic insulin levels, tumor-carrying mice were subjected to one of the following conditions: i) Untreated, ii) single injection of the β-cell toxin streptozotosin prior to cancer cell transplantation and iii) daily injection of insulin following cancer cell transplantation. After 12 weeks, tumor viability was assessed by histological analysis. Western blotting of the tumor grafts was performed to determine the protein expression levels of insulin receptor (IR) and two downstream proteins, hexokinase-II (HK-II) and vascular endothelial growth factor (VEGF). Histologically, the greatest viability was observed in wt-MiaPaCa2 tumors with carriers that remained untreated. These tumors also exhibited greater IR expression than their si-MiaPaCa2 counterparts, indicating that HIF-1 is necessary for basal expression of IR. However, IR expression was increased in wt-MiaPaCa2 and si-MiaPaCa2 tumors when the carriers were treated with exogenous insulin. This indicates that the insulin-induced IR expression was independent of HIF-1. Notably, the insulin-induced IR expression was associated with increased HK-II and VEGF expression in wt-MiaPaCa2 tumors but not si-MiaPaC2 tumors. Therefore, the present study proposes that insulin and HIF-1 may cooperate to increase pancreatic cancer cell viability. Furthermore, the HIF-1 signaling pathway is required for insulin-induced HK-II and VEGF expression, as well as basal IR expression levels in pancreatic cancer cells.
本研究的目的是调查间质胰岛素与癌症诱导的缺氧诱导因子-1（HIF-1）在胰腺癌细胞中是否协同作用。45只裸鼠被分为一个完整对照组和六个胰腺肿瘤携带组。在三个携带组中使用HIF-1阳性野生型MiaPaCa2（wt-MiaPaCa2）胰腺癌细胞生成胰腺肿瘤，在另外三个携带组中使用转染了针对HIF-1α的小干扰RNA的MiaPaCa2细胞（si-MiaPaCa2细胞）。为了改变胰腺内胰岛素水平，携带肿瘤的小鼠接受以下条件之一：i）未治疗，ii）在癌细胞移植前单次注射β细胞毒素链脲佐菌素，iii）在癌细胞移植后每日注射胰岛素。12周后，通过组织学分析评估肿瘤活力。对肿瘤移植物进行蛋白质印迹分析，以确定胰岛素受体（IR）以及两个下游蛋白己糖激酶-II（HK-II）和血管内皮生长因子（VEGF）的蛋白表达水平。组织学上，在未治疗的携带肿瘤的wt-MiaPaCa2肿瘤中观察到最大的活力。这些肿瘤也比其对应的si-MiaPaCa2肿瘤表现出更高的IR表达，表明HIF-1是IR基础表达所必需的。然而，当携带肿瘤的小鼠接受外源性胰岛素治疗时，wt-MiaPaCa2和si-MiaPaCa2肿瘤中的IR表达均增加。这表明胰岛素诱导的IR表达独立于HIF-1。值得注意的是，胰岛素诱导的IR表达与wt-MiaPaCa2肿瘤中HK-II和VEGF表达增加相关，但与si-MiaPaC2肿瘤无关。因此，本研究提出胰岛素和HIF-1可能协同作用以增加胰腺癌细胞活力。此外，HIF-1信号通路是胰岛素诱导的HK-II和VEGF表达以及胰腺癌细胞中IR基础表达水平所必需的。
