IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.

Authors

Roberta Matà, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
Chiara Palladino, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, ItalyFollow
Maria Luisa Nicolosi, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
Anna Rita Lo Presti, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
Roberta Malaguarnera, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, ItalyFollow
Marco Ragusa, Department of Biomedical and Biotechnological Sciences Biology, Genetics and BioInformatics Unit, University of Catania, Catania, ItalyFollow
Daniela Sciortino, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
Andrea Morrione, Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United StatesFollow
Marcello Maggiolini, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, ItalyFollow
Veronica Vella, School of Human and Social Sciences, 'Kore' University of Enna, Italy; Department of Clinical and Molecular Bio-Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Medical Center, Catania, ItalyFollow
Antonino Belfiore, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, ItalyFollow

Document Type

Article

Publication Date

12-9-2015

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 7, Issue 7, 2016, Pages 7683-7700.

The published version is available at DOI: 10.18632/oncotarget.6524

Copyright © 2015 The Authors

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.

Recommended Citation

Matà, Roberta; Palladino, Chiara; Nicolosi, Maria Luisa; Presti, Anna Rita Lo; Malaguarnera, Roberta; Ragusa, Marco; Sciortino, Daniela; Morrione, Andrea; Maggiolini, Marcello; Vella, Veronica; and Belfiore, Antonino, "IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway." (2015). Kimmel Cancer Center Faculty Papers. Paper 58.
https://jdc.jefferson.edu/kimmelccfp/58

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

PubMed ID

26655502