Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration.
Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration.
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前梯度 2 (AGR2) 的诱导在胰岛素样生长因子 1 (IGF-1) 诱导的乳腺癌细胞增殖和迁移中发挥关键作用
DOI：
10.1007/s12032-015-0577-z
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发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Li Z;Wu Z;Chen H;Zhu Q;Gao G;Hu L;Negi H;Kamle S;Li D
前梯度 2 (AGR2) 是一种有前景的抗肿瘤靶点，与雌激素受体表达和乳腺癌转移进展相关。胰岛素样生长因子-1 (IGF-1) 是刺激乳腺癌进展并介导抗雌激素耐药性的另一种有效因子。然而，这两个因素在乳腺癌耐药中的确切机制和联系尚未完全阐明。在这里，我们首次破译IGF-1通过-802和-808 bp之间的雌激素反应元件（ERE）和位于AGR2启动子上-972和-982 bp之间的亮氨酸拉链转录因子结合位点在MCF7细胞系中显着诱导AGR2。我们还发现 ERK1/2 和 AKT 通路在 ERE 上游介导雌激素受体-α，而 JNK 通路通过 c-Jun/c-Fos 复合物激活亮氨酸拉链位点。此外，我们的数据表明，AGR2 的敲低可减少 IGF-1 诱导的细胞增殖、迁移和细胞周期进展。因此，我们报告 AGR2 是参与 IGF-1 诱导的乳腺癌发展的关键调节剂。我们认为，鉴定 IGF-1/胰岛素信号和 AGR2 启动子激活之间的联系机制非常重要，因为它为抗乳腺癌药物的开发提供了见解。
Anterior gradient 2 (AGR2) is a promising anti-tumor target associated with estrogen receptor expression and metastatic progression of breast cancer. Insulin-like growth factor-1 (IGF-1) is another potent factor that stimulates breast cancer progression and mediates anti-estrogen drug resistance. However, the precise mechanism and connections between these two factors in breast cancer drug resistance have not been fully elucidated. Here, for the first time, we decipher that IGF-1 remarkably induces AGR2 in the MCF7 cell line, through an estrogen response element (ERE) between −802 and −808 bp and a leucine zipper transcription factor-binding site located between −972 and −982 bp on the AGR2 promoter. We also found that the ERK1/2 and AKT pathways mediate estrogen receptor-α at the upstream of ERE and that the JNK pathway activates the leucine zipper site through the c-Jun/c-Fos complex. Additionally, our data suggest that knockdown of AGR2 reduces IGF-1-induced cell proliferation, migration and cell cycle progression. Therefore, we report that AGR2 is a key modulator involved in IGF-1-induced breast cancer development. We propose that the identification of the mechanism linking the IGF-1/insulin signal and AGR2 promoter activation is important, because it provides insights into the development of anti-breast cancer drugs.
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