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Insulin-like growth factor-I regulates GPER expression and function in cancer cells

Oncogene volume 32, pages 678–688 (2013)Cite this article

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Abstract

Functional cross talk between insulin-like growth factor-I (IGF-I) system and estrogen signaling has been largely reported, although the underlying molecular mechanisms remain to be fully elucidated. As GPR30/GPER mediates rapid cell responses to estrogens, we evaluated the potential of IGF-I to regulate GPER expression and function in estrogen receptor (ER)α-positive breast (MCF-7) and endometrial (Ishikawa) cancer cells. We found that IGF-I transactivates the GPER promoter sequence and upregulates GPER mRNA and protein levels in both cells types. Similar data were found, at least in part, in carcinoma-associated fibroblasts. The upregulation of GPER expression by IGF-I involved the IGF-IR/PKCδ/ERK/c-fos/AP1 transduction pathway and required ERα, as ascertained by specific pharmacological inhibitors and gene-silencing. In both MCF-7 and Ishikawa cancer cells, the IGF-I-dependent cell migration required GPER and its main target gene CTGF, whereas the IGF-I-induced proliferation required both GPER and cyclin D1. Our data demonstrate that the IGF-I system regulates GPER expression and function, triggering the activation of a signaling network that leads to the migration and proliferation of cancer cells.

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Acknowledgements

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, project no. 8925/2009 to MM and project no. 10625/2009 to AB; project Calabria 2011 to AB and MM) (http://www.airc.it/), Fondazione Cassa di Risparmio di Calabria e Lucania and Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project PRIN 2008PK2WCW/2008 to MM and project PRIN 2008BKRFBH_005 to AB) (http://www.istruzione.it/).

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Authors and Affiliations

  1. Department of Pharmaco-Biology, University of Calabria, Rende, Italy

    P De Marco, V Bartella, A Vivacqua, R Lappano, M F Santolla, V Pezzi & M Maggiolini

  2. Endocrinology,

    A Morcavallo & A Belfiore

  3. Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

    A Morcavallo & A Belfiore

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  1. P De Marco
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Correspondence to M Maggiolini.

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De Marco, P., Bartella, V., Vivacqua, A. et al. Insulin-like growth factor-I regulates GPER expression and function in cancer cells. Oncogene 32, 678–688 (2013). https://doi.org/10.1038/onc.2012.97

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