Aizen Daniel, Pasmanik-Chor Metsada, Sarfstein Rive, Laron Zvi, Bruchim Ilan, Werner Haim
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Bioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Front Endocrinol (Lausanne). 2018 Mar 20;9:105. doi: 10.3389/fendo.2018.00105. eCollection 2018.
Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent upregulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross-linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastases are probably the main factor contributing to tumor invasiveness, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in oncology. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogs with respect to native insulin.
胰岛素类似物的研发旨在改善糖尿病治疗。然而，胰岛素分子中引入的某些修饰被证明会增强其对胰岛素样生长因子-1受体（IGF1R）的亲和力。包括子宫内膜癌在内的大多数肿瘤都高表达IGF1R。本研究旨在确定在1型和2型子宫内膜癌细胞系（分别为ECC-1和USPC-1）中，与胰岛素和IGF1相比，甘精胰岛素或地特胰岛素差异激活的所有基因。全基因表达分析表明，在两种子宫内膜癌细胞类型中，细丝蛋白-A（FLNA）（一种编码肌动蛋白丝交联蛋白的基因）的表达呈配体依赖性上调。与迁移实验相关的沉默实验证实了FLNA在细胞生长和运动中的作用。我们的数据表明，甘精胰岛素激活不同的基因集可能会导致特定途径的刺激，或者可能提供不同于胰岛素经典诱导效应的累加效应。鉴于转移可能是导致肿瘤侵袭性的主要因素，将FLNA鉴定为胰岛素样激素的下游靶点可能在肿瘤学中具有转化意义。子宫内膜癌的临床研究可能会提供更多关于胰岛素类似物相对于天然胰岛素可能存在的差异作用的相关信息。
