Insulin-like growth factor-I regulates GPER expression and function in cancer cells
Insulin-like growth factor-I regulates GPER expression and function in cancer cells
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DOI：
10.1038/onc.2012.97
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发表时间：
2013-02-07
期刊：
影响因子：
8
通讯作者：
Maggiolini, M.
中科院分区：
文献类型：
--
作者：
De Marco, P.;Bartella, V.;Maggiolini, M.
胰岛素样生长因子-I（IGF-I）系统与雌激素信号转导之间的功能性串扰已被大量报道，但其潜在的分子机制仍有待充分阐明。由于GPR 30/GPER介导对雌激素的快速细胞反应，我们评估了IGF-I调节雌激素受体（ER）α阳性乳腺癌（MCF-7）和子宫内膜癌（石川）细胞中GPER表达和功能的潜力。我们发现，IGF-I反式激活GPER启动子序列和上调GPER mRNA和蛋白水平在两种细胞类型。在癌相关成纤维细胞中也发现了类似的数据，至少部分如此。IGF-I对GPER表达的上调涉及IGF-IR/PKC δ/ERK/c-fos/AP 1转导途径，并需要ER α，这一点通过特异性药理学抑制剂和基因沉默来确定。在MCF-7和石川癌细胞中，IGF-I依赖的细胞迁移需要GPER及其主要靶基因CTGF，而IGF-I诱导的增殖需要GPER和细胞周期蛋白D1。我们的数据表明，IGF-I系统调节GPER的表达和功能，触发信号网络的激活，导致癌细胞的迁移和增殖。Oncogene（2013）32，678-688; doi：10.1038/onc.2012.97; 2012年3月19日在线发表
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)alpha-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/PKC delta/ERK/c-fos/AP1 transduction pathway and required ER alpha, 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. Oncogene (2013) 32, 678-688; doi:10.1038/onc.2012.97; published online 19 March 2012