ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer.
ErbB3 binding protein 1 represses metastasis-promoting gene anterior gradient protein 2 in prostate cancer.
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DOI：
10.1158/0008-5472.can-09-2904
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Hamburger AW
中科院分区：
文献类型：
--
作者：
Zhang Y;Ali TZ;Zhou H;D'Souza DR;Lu Y;Jaffe J;Liu Z;Passaniti A;Hamburger AW
发育调节的前梯度蛋白2（AGR 2）基因的异常激活与转移表型相关。然而，其作用机制及其在前列腺癌中的调节尚不清楚。我们以前发现ErbB 3结合蛋白1（EBP 1），其表达在前列腺癌中减少，是AGR 2的假定阻遏物。目前的研究表明，AGR 2的过表达促进了非转移性LNCaP细胞的运动性和侵袭性，而在转移性LNCaP衍生物C4-2B细胞中AGR 2的沉默显著降低了细胞侵袭性，这表明AGR 2是人类前列腺癌侵袭能力的重要决定因素。此外，我们提供的证据表明，EBP 1的抗侵袭作用至少部分是通过其抑制AGR 2表达的能力而发生的。EBP 1抑制AGR 2基因的启动子活性，下调Foxa 1和Foxa 2刺激的AGR 2转录并降低转移行为。相反，EBP 1的消融上调AGR 2基因的表达，增强Foxa 1和Foxa 2刺激的AGR 2启动子活性，并导致更具转移性的表型。我们还发现前列腺癌细胞系和重要的原发性前列腺肿瘤中EBP 1和AGR 2水平之间存在显著的负相关性。总的来说，我们的研究结果突出了以前未表征的EBP 1-Foxa-AGR 2信号通路，其在转移性前列腺癌的治疗管理中具有潜在的机制和功能意义。
The aberrant activation of the developmentally regulated anterior gradient protein 2 (AGR2) gene has been associated with a metastatic phenotype. However, its mechanism of action and its regulation in prostate cancer is unknown. We had previously found that the ErbB3 binding protein 1 (EBP1), whose expression is reduced in prostate cancer, is a putative repressor of AGR2. The current study demonstrates that overexpression of AGR2 promotes the motility and invasiveness of non-metastatic LNCaP cells, while silencing of AGR2 in metastatic LNCaP derivative C4–2B cells significantly reduced cell invasion, suggesting AGR2 is an important determinant of the invasive capacity in human prostate cancer. Further, we provide evidence that the anti-invasive effect of EBP1 occurs, at least in part, through its ability to inhibit the expression of AGR2. EBP1 suppresses the promoter activity of the AGR2 gene, downregulates Foxa1 & Foxa2-stimulated AGR2 transcription and decreases metastatic behavior. In contrast, ablation of EBP1 upregulates the expression of the AGR2 gene, enhances Foxa1 and Foxa2–stimulated AGR2 promoter activity, and results in a more metastatic phenotype. We also found a significant inverse correlation between EBP1 and AGR2 levels in prostate cancer cell lines and importantly, primary prostate tumors. Collectively, our results highlight a previously uncharacterized EBP1-Foxa-AGR2 signaling circuit that has potential mechanistic and functional significance in therapeutic management of metastatic prostate cancer.