Dottorato di Ricerca in Medicina Traslazionale. Ciclo XXIXInsulin-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 IGFI
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 strategiesUniversità della Calabri
