Research Papers: Pathology:

Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells

Silvia Avino, Paola De Marco, Francesca Cirillo, Maria Francesca Santolla, Ernestina Marianna De Francesco, Maria Grazia Perri, Damiano Rigiracciolo, Vincenza Dolce, Antonino Belfiore, Marcello Maggiolini _, Rosamaria Lappano and Adele Vivacqua

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Oncotarget. 2016; 7:52710-52728. https://doi.org/10.18632/oncotarget.10348

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Silvia Avino1,*, Paola De Marco1,*, Francesca Cirillo1, Maria Francesca Santolla1, Ernestina Marianna De Francesco1, Maria Grazia Perri1, Damiano Rigiracciolo1, Vincenza Dolce1, Antonino Belfiore2, Marcello Maggiolini1, Rosamaria Lappano1,** and Adele Vivacqua1,**

1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy

2 Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy

* These authors have contributed equally to this work

** Joint senior Authors

Correspondence to:

Marcello Maggiolini, email:

Keywords: DDR1, GPER, IGF-I, IGF-IR, mesothelioma, lung cancer, Pathology Section

Received: April 06, 2016 Accepted: June 17, 2016 Published: June 30, 2016


Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies.

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