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.
Highlights
The IGF system has a crucial role in the regulation of mammalian development and growth [1, 2, 3]
In murine fibroblasts transfected with the human IGF-I receptor (IGF-insulin receptor (IR)), the concomitant overexpression of Discoidin Domain Receptor 1 (DDR1) markedly enhanced IGF-IR protein expression and IGF-I-dependent colony formation
Both in breast cancer cells and transfected fibroblasts, IGF-I stimulation induced rapid tyrosinephosphorylation of DDR1, which was accompanied by increased association of the DDR1 – IGF-IR complex, rapid internalization and sorting to early endosomes [18]
Summary
The IGF system has a crucial role in the regulation of mammalian development and growth [1, 2, 3]. The two main receptors of the system, the type I IGF-I receptor (IGF-IR) and the homolog insulin receptor (IR), which occurs in two isoforms (IR-A and IR-B), are often overexpresssed in cancer cells and may affect the early phases of carcinogenesis and cancer progression and cancer resistance to therapies [4,5,6,7,8,9]. Their cognate ligands, IGF-I and IGF-II, are frequently abundant in the tumor microenvironment as they can be secreted by the tumor stroma and/or by malignant cells [10, 11]. The recent results of phase 2 and phase 3 trials with IGF-IR blocking agents have been largely disappointing [14,15,16]
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