Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
School of Human and Social Science, University "Kore" of Enna, 94100 Enna, Italy.
Int J Mol Sci. 2018 Nov 16;19(11):3615. doi: 10.3390/ijms19113615.
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
胰岛素受体 (IR) 介导代谢和有丝分裂效应，尤其是在代谢途径抵抗的情况下，如肥胖型糖尿病，会发生代偿性高胰岛素血症而过度表达。在许多癌症中，IR 通过外显子 11 的选择性剪接优先过度表达为 IR-A 同工型。IR-A 的过度表达和 IR-A:IR-B 比值的增加是促进癌细胞对胰岛素和 IGF-2 有丝分裂反应的机制，IGF-2 由上皮和基质癌细胞局部产生。在癌症中，IR-A 同工型优势可能是由于 mRNA 转录和转录后水平的失调，包括剪接因子、非编码 RNA 和蛋白质降解。调节 IR 同工型表达的机制很复杂，尚未完全阐明。IR 同工型的过度表达可能在癌细胞干性、肿瘤进展和对靶向治疗的耐药性中发挥作用。从临床角度来看，癌症中 IR-A 的过度表达可能是导致 IGF-1R 靶向治疗耐药的决定因素。癌症中 IR 同工型的表达可能具有预测生物标志物的意义，联合靶向 IGF-1R 和 IR-A 可能代表一种新的更有效的治疗策略。
