IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor
IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor
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DOI：
10.1016/j.canlet.2017.11.039
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发表时间：
2018-02-28
期刊：
影响因子：
9.7
通讯作者：
Hong, Suntaek
中科院分区：
文献类型：
--
作者：
Kim, Hye-Youn;Huyen Trang Ha Thi;Hong, Suntaek
三阴性乳腺癌（TNBC）是最具侵袭性的恶性肿瘤之一，由于缺乏有效的治疗靶点，死亡率很高。在本研究中，我们证明胰岛素样生长因子-II mRNA 结合蛋白 2 和 3（IMP2 和 IMP3）在 TNBC 中特异性过表达，并协同促进细胞迁移和侵袭。研究发现，TNBC 细胞中 IMP2 和 IMP3 的下调可在抑制细胞侵袭和侵袭伪足形成方面产生协同作用，而管腔亚型细胞中 IMP2 和 IMP3 的过表达可增强上皮间质转化和转移。我们还表明，IMP2 和 IMP3 是 microRNA-200a (miR-200a) 的直接靶标，而 microRNA-200a 在 TNBC 中表达下调。相反，IMP2 和 IMP3 通过招募 CCR4-NOT 转录复合物亚基 1 (CNOT1) 复合物来破坏孕酮受体 (PR) mRNA 的稳定性，从而抑制 miR-200a 的转录。总之，我们的研究结果表明，IMP2 和 IMP3 部分决定了特征表型，并通过下调 PR 协同促进 TNBC 的转移。确定的 IMP2/3-miR-200a-PR 轴代表了一种新型的双负反馈环，可作为治疗 TNBC 的新的潜在治疗靶点。 (C) 2017 Elsevier B.V. 保留所有权利。
Triple-negative breast cancer (TNBC) is one of the most aggressive malignancies and is associated with high mortality rates due to the lack of effective therapeutic targets. In this study, we demonstrated that insulin-like growth factor-II mRNA-binding protein 2 and 3 (IMP2 and IMP3) are specifically overexpressed in TNBC and cooperate to promote cell migration and invasion. Downregulation of both IMP2 and IMP3 in TNBC cells was found to produce a synergistic effect in suppressing cell invasion and invadopodia formation, whereas overexpression of IMP2 and IMP3 in luminal subtype cells enhanced epithelial-mesenchymal transition and metastasis. We also showed that IMP2 and IMP3 are direct targets of microRNA-200a (miR-200a), which is downregulated in TNBC. Conversely, IMP2 and IMP3 suppressed the transcription of miR-200a by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex subunit 1 (CNOT1) complex. Together, our findings suggest that IMP2 and IMP3 partially determine the characteristic phenotype and synergistically promote the metastasis of TNBC by downregulating PR. The identified IMP2/3-miR-200a-PR axis represents a novel double-negative feedback loop and serves as a new potential therapeutic target for the treatment of TNBC. (C) 2017 Elsevier B.V. All rights reserved.