Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells.
Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells.
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DOI：
10.18632/oncotarget.10348
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发表时间：
2016-08-16
期刊：
影响因子：
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通讯作者：
Vivacqua A
中科院分区：
文献类型：
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作者：
Avino S;De Marco P;Cirillo F;Santolla MF;De Francesco EM;Perri MG;Rigiracciolo D;Dolce V;Belfiore A;Maggiolini M;Lappano R;Vivacqua A
胰岛素样生长因子-I（IGF-I）/IGF-I受体（IGF-IR）系统在多种肿瘤的发生、发展中起着重要作用。我们先前已经证明IGF-IR与G蛋白雌激素受体（GPER）和胶原蛋白受体盘状结构域1（DDR 1）合作，这些都与癌症进展有关。在这里，我们提供了新的证据，通过IGF-I/IGF-IR信号触发与GPER和DDR 1在间皮瘤和肺癌细胞的功能性串扰的分子机制。特别地，我们表明IGF-I激活由IGF-IR介导的转导网络，导致GPER及其主要靶基因CTGF和EGFR 1的上调以及DDR 1靶基因如MATN-2、FBN-1、NOTCH 1和HES-1的诱导。值得注意的是，某些DDR 1介导的对IGF-I刺激的作用需要IGF-IR和GPER两者，如所确定的敲低这些受体的表达。上述发现很好地概括了重要的生物学结果，如IGF-I促进间皮瘤和肺癌细胞的趋化性和迁移。总体而言，我们的数据表明，IGF-I/IGF-IR系统触发刺激作用，通过GPER和DDR 1在侵袭性肿瘤，如间皮瘤和肺肿瘤。因此，这种新的信号通路可能代表了制定创新抗癌策略的进一步目标。
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.