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Abstract
Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform- and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors.
Highlights
Insulin resistance has been associated with a variety of insulin receptor (IR) signaling defects [1,2]
The biological impact of paralog and isoform switching in IR in upstream regulatory (IGF-II) and downstream signal modulators under those clinical conditions sharing insulin-resistance, hyperinsulinemia, and chronic hypoxic states along with their link to cancer development is just emerging
A clear scenario suggested by evidences reviewed implies that the IR isoform A specific expression constitutes an early driver for the cancer-malignant transition
Summary
Insulin resistance has been associated with a variety of insulin receptor (IR) signaling defects [1,2]. In spite of a general reduction in IR levels in insulin-resistant states [19], the IR-A/IR-B ratio is increased in several tissues [20], supporting the scenario proposed in Figure 1 for the role of the IGF-II-IR-A axis in linking obesity/type 2 diabetes and cancer development. At present, our knowledge on the role of alternative splicing and paralog genes switch of signaling components involving insulin-resistance-associated conditions is limited (since most studies focus on full-length native proteins) (Table 1), the growing evidence linking hypoxia to differential isoform and/or paralog expression may provide the rationale to functionally connect these gene product variants with specific abnormalities observed in obese and type 2 diabetic patients in light of the chronic exposure of tissues to hypoxia (e.g., in adipose tissue) occurring under these conditions [24,25]. Tchaencgerro-wprionmg ofitnindgingfusn, schtioown iancgtidviaffteedrenthtiraoluIGghF-tIhI etaIrRge-Ats wbuitthncoatncveiar-pinrosumliontinogn ftuhnectsiaomn eacrteivceaptetdor th[1r5o,u2g9h], tnhoerIRb-yAtbhuet InGoFt v1Ria i[n3s0u],lifnuortnhtehressuapmpeorretcesputcohr [v1i5e,w29]a,nndorpboyintht eaItGtFh1eRIR[3-0A], feuxrpthreesrssiounppaosrta spuochssvibielewfuanndctipoonianlt daitstchreimIRin-Aanetxbpertewsseieonn daisaabeptoesssaibnlde fcuannccteironanalddaisvcarilmidinbaionmt baerktwereefonrdciaanbceetersaalonndg cwanitcheroathnedraesvtaalbidlisbhieodmbairokmerafrokrecrsa.ncer along with other established biomarkers
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