Abstract
Insulin-like growth factor 2 (IGF2) mRNA-binding protein 3 (IGF2BP3) is an oncofetal protein that binds RNA, thereby influencing the fate of target transcripts. IGF2BP3 is synthesized de novo in cancer, where it promotes proliferation, drug resistance, and metastasis via both IGF2-dependent and IGF2-independent mechanisms. Ewing sarcoma (ES) is a rare bone and soft tissue tumor in which the IGF system plays a pivotal role. This study aimed to investigate the effect of IGF2BP3 on the regulation of the IGF system in ES. Among the components of the IGF axis, a direct significant correlation was identified between IGF2BP3 and IGF1R at mRNA and protein levels in two independent series of clinical specimens from patients with localized ES. After the formal demonstration of a direct association between IGF2BP3 and IGF1R mRNA using ribo-immunoprecipitation assay, we performed in vitro studies using A673 and TC-71 ES cell lines to demonstrate that IGF2BP3 loss promotes the downregulation of IGF1R and a decreased biological response to IGF1, represented by reduced migration and cell growth. Additionally, the compensatory activation of insulin receptor (IR) and its mitogenic ligand IGF2 is triggered in some but not all cell lines in response to IGF2BP3-mediated IGF1R loss. These findings have therapeutic implications because cells with a decreased expression of IGF2BP3/IGF1R axis but an increased expression of the IR/IGF2 loop display higher sensitivity to the dual inhibitor OSI-906 than do control cells. Therefore, studies on IGF2BP3, which was confirmed as a post-transcriptional regulator of IGF1R, provide a step forward in the identification of new mechanisms regulating the IGF system. In addition, our results demonstrate that the detection of IGF2BP3 expression should be combined with the assessment of the IGF1R/IR ratio to predict cell responses to anti-IGF1R/IR agents.
Highlights
Insulin-like growth factor 2 (IGF2) mRNA-binding proteins (IGF2BPs) represent a family of oncofetal RNA-binding proteins (RBPs), including the paralogs IGF2BP1, 2, and 3, which control the localization, translation, and stability of mRNAs [1]
IGF2BP3 expression was not correlated with IGF2 expression (Figure 1A), but a direct correlation was found between IGF1R and IGF2BP3 expression (Figure 1B)
Even the failed studies included patients who received some benefit, especially Ewing sarcoma (ES) patients. This evidence confirmed the therapeutic importance of the IGF1R pathway, but on the other, it supported the need for deeper insights into the IGF system to help the identification of biomarkers of response [reviewed in Ref. [41]]
Summary
Insulin-like growth factor 2 (IGF2) mRNA-binding proteins (IGF2BPs) represent a family of oncofetal RNA-binding proteins (RBPs), including the paralogs IGF2BP1, 2, and 3, which control the localization, translation, and stability of mRNAs [1]. IGF2BPs are mainly expressed during embryogenesis and absent in adult tissues [2, 3], but in vitro studies have demonstrated that IGF2BP1 and 3 are IGF2BP3 Regulates IGF1R in ES synthesized de novo in cancer, where they act as oncogenes promoting malignant processes including cell polarization, migration, morphological determination, proliferation, differentiation, and drug sensitivity [4,5,6,7,8]. The comprehensive identification of IGF2BP targets is still under investigation, but the network of RNAs whose stability is regulated by each IGF2BP may predict the phenotype of IGF2BP-expressing cells and determine the involvement of these proteins in various crucial cellular functions [reviewed in Ref. IGF signaling, involving IGF1R, has become an attractive target for the development of novel anticancer agents
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