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IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway
Mata, Roberta Palladino, Chiara Nicolosi, Maria Luisa Lo Presti, Anna Rita Malaguarnera, Roberta Ragusa, Marco Sciortino, Daniela Vella, Veronica Belfiore, Antonino
Mata, Roberta
Palladino, Chiara
Nicolosi, Maria Luisa
Lo Presti, Anna Rita
Malaguarnera, Roberta
Ragusa, Marco
Sciortino, Daniela
Vella, Veronica
Belfiore, Antonino
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2015-12-09
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Biology
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https://doi.org/10.18632/oncotarget.6524
Abstract
Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer. In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I. These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis.
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Matà R., Palladino C., Nicolosi M. Luisa, Presti A. Rita Lo, Malaguarnera R., Ragusa M., Sciortino D., Morrione A., Maggiolini M., Vella V., Belfiore A. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2016; 7: 7683-7700. Retrieved from https://www.oncotarget.com/article/6524/text/
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Oncotarget, Vol. 7, No. 8
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