Pivovarova Olga, von Loeffelholz Christian, Ilkavets Iryna, Sticht Carsten, Zhuk Sergei, Murahovschi Veronica, Lukowski Sonja, Döcke Stephanie, Kriebel Jennifer, de las Heras Gala Tonia, Malashicheva Anna, Kostareva Anna, Lock Johan F, Stockmann Martin, Grallert Harald, Gretz Norbert, Dooley Steven, Pfeiffer Andreas F H, Rudovich Natalia
a Department of Clinical Nutrition ; German Institute of Human Nutrition Potsdam-Rehbruecke ; Nuthetal , Germany.
Cell Cycle. 2015;14(14):2293-300. doi: 10.1080/15384101.2015.1046647. Epub 2015 May 6.
Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n = 22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis.
2型糖尿病（T2DM）、胰岛素治疗和高胰岛素血症是肝癌的独立危险因素。最近，有人提出使用一种新型胰岛素降解酶（IDE）抑制剂作为T2DM的一种新治疗策略。然而，抑制IDE可能会通过增加细胞内胰岛素浓度来刺激肝细胞增殖。本研究的目的是表征抑制HepG2肝癌细胞中IDE活性的作用，并分析T2DM患者肝脏中IDE的特异性表达。使用IDE RNAi抑制或不抑制IDE活性，将HepG2细胞用10 nM胰岛素处理24小时，然后分析细胞转录组和增殖率。使用人类肝脏样本（n = 22）通过微阵列进行基因表达谱分析。在HepG2细胞中，敲低IDE会改变参与细胞周期和凋亡途径的基因表达。敲低IDE的细胞增殖率低于对照组。微阵列分析显示，T2DM患者肝脏中IDE表达降低，同时p53依赖性基因FAS和CCNG2下调，但增殖标志物MKI67、MCM2和PCNA未上调。在来自GEO Profiles数据库的肝脏微阵列数据集中也发现了类似结果。总之，T2DM患者肝脏中IDE表达降低，同时p53通路失调。对于T2DM治疗长期使用IDE抑制剂对肝脏肿瘤发生的潜在影响，应在动物研究中进行仔细测试。
