MiR-449a promotes breast cancer progression by targeting CRIP2.
MiR-449a promotes breast cancer progression by targeting CRIP2.
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MiR-449a 通过靶向 CRIP2 促进乳腺癌进展。
DOI：
10.18632/oncotarget.7753
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Liu FF
中科院分区：
文献类型：
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作者：
Shi W;Bruce J;Lee M;Yue S;Rowe M;Pintilie M;Kogo R;Bissey PA;Fyles A;Yip KW;Liu FF
预后生物标志物的鉴定及其潜在作用机制仍然引起乳腺癌生物学的极大兴趣。通过对 71 个淋巴结阴性的浸润性导管乳腺癌和 5 个正常乳腺上皮组织的整体 miRNA 分析，我们发现 miR-449a 在恶性乳腺组织中高度过表达。其表达与患者复发率增加、总生存率降低和无病生存率降低显着相关。在体外，miR-449a 促进乳腺癌细胞增殖、克隆存活、迁移和侵袭。通过利用三模态计算机方法进行靶标鉴定，富含半胱氨酸的蛋白 2（CRIP2；一种转录因子）被鉴定为 miR-449a 的直接靶标，并通过 qRT-PCR、Western blot 和荧光素酶报告基因检测得到证实。稳定转染 CRIP2 的 MDA-MB-231 细胞在小鼠异种移植模型中表现出细胞活力、迁移和侵袭显着降低，以及肿瘤生长和血管生成减少。我们的数据显示，miR-449a 的过度表达会抑制 CRIP2，然后 CRIP2 可能通过 NF-κB/p65 复合物介导的 VEGF 转录影响肿瘤脉管系统。这些发现定义了 miR-449a 在人类乳腺癌中的致癌功能，并强调了该通路在驱动攻击行为中的重要性。
The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.