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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Front+Endocrinol+(Lausanne)
2018 ; 9
(ä): 178
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Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Influences Sensitivity to
Anti-IGF System Agents Through the Translational Regulation of IGF1R
#MMPMID29731738
Mancarella C
; Pasello M
; Manara MC
; Toracchio L
; Sciandra EF
; Picci P
; Scotlandi K
Front Endocrinol (Lausanne)
2018[]; 9
(ä): 178
PMID29731738
show ga
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.