microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7
microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7
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DOI：
10.1089/dna.2016.3282
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发表时间：
2016-09-01
影响因子：
3.1
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
--
作者：
Liu, Jingjing;Zhou, Yang;Zhang, Jin
作为TGF-β信号传导的抑制剂，SMAD 7被报道在乳腺癌的发生和进展中发挥双重作用。它通过阻断上皮-间质转化抑制肿瘤转移，但其在其他肿瘤过程中的作用研究较少。在这项研究中，发现乳腺癌组织中miR-497表达与SMAD 7表达呈负相关。生物信息学分析在SMAD 7的3'非翻译区内定义了一个潜在的miR-497应答元件，该元件在报告基因实验中得到验证。MTT法和侵袭实验显示，miR-497的高表达及SMAD 7的减少抑制了MDA-MB-231和MCF-7乳腺癌细胞的生长，流式细胞仪检测到miR-497的高表达诱导了S期阻滞。此外，通过模拟物处理上调miR-497表达显著抑制原位裸鼠模型中的肿瘤生长。最后，Kaplan-Meier检验表明，miR-497的高表达可带来更好的预后，特别是在HER 2过表达和三阴性乳腺癌（TNBC）中。综上所述，我们的研究结果确定了SMAD 7在乳腺癌中的增殖促进作用，因此确定了miR-497通过转录后机制对SMAD 7在乳腺癌中的调节作用。此外，miR-497有望成为治疗HER 2阳性和TNBC的新靶点。
As an inhibitor of TGF-beta signaling, SMAD7 was reported to play dual roles in breast cancer development and progression. It inhibited the cancer metastasis by blocking epithelial-mesenchymal transition, however, litter studies focused on its role in other cancer processes. In this study, miR-497 expression was found inversely correlated with SMAD7 expression in breast cancer tissues. Bioinformatics analyses defined a potential miR-497 response element within 3' untranslated region of SMAD7 that was validated in reporter gene experiments. Enforced miR-497 expression, accompanied with SMAD7 reduction, suppressed MDA-MB-231 and MCF-7 breast cancer cell growth by MTT and invasion assay, and, induced the S phase arrest detected by flow cytometry. Furthermore, upregulated miR-497 expression by mimics treatment significantly suppressed the tumor growth in the orthotopic nude mouse models. Finally, high expression of miR-497 conferred a better prognosis, indicated by Kaplan-Meier test, especially in HER2 overexpression and triple-negative breast cancer (TNBC). Taken together, our results identified the proliferation promoting role of SMAD7 in breast cancer and therefore established the regulations of SMAD7 in breast cancer by miR-497 through a posttranscriptional mechanism. Moreover, miR-497 might be deemed as a novel potential therapeutic target for the HER2 positive and TNBC in future.