title: IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.
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.
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Matà
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Palladino
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Nicolosi
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Lo Presti
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Malaguarnera
authors.affiliation: Department of Biomedical and Biotechnological Sciences Biology, Genetics and BioInformatics Unit, University of Catania, Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ragusa
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sciortino
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.affiliation: Motor Sciences, School of Human and Social Sciences, "Kore" University of Enna, Enna, Italy.|Department of Clinical and Molecular Bio-Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Vella
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C531408:mirn199 microRNA, human; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D051057:Proto-Oncogene Proteins c-akt
keywords: DDR1; IGF-IR; breast cancer; insulin-like growth factor-I receptor