Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong, China. State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Centre, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Vascular and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Cancer Res. 2016 Mar 1;76(5):1101-11. doi: 10.1158/0008-5472.CAN-15-1770. Epub 2016 Jan 8.
The strength and duration of NF-κB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-κB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-κB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-κB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy.
在生理条件下，NF-κB 信号的强度和持续时间在多个水平上受到严格控制，但癌症中 NF-κB 途径的组成性激活的机制仍不清楚。在这项研究中，我们研究了 miRNA 对乳腺癌中 NF-κB 级联的调节。我们报告说，miR-892b 在人乳腺癌标本中的表达明显下调，并与患者预后不良相关。在乳腺癌细胞中过表达 miR-892b 可显著降低肿瘤生长、转移能力和诱导血管生成的能力，而 miR-892b 耗竭则增强了这些特性，无论是在体外还是在体内。此外，我们证明 miR-892b 通过直接靶向和抑制 NF-κB 的多个介质，包括 TRAF2、TAK1 和 TAB3，来减弱 NF-κB 信号，因此，乳腺癌细胞中 miR-892b 的沉默维持了 NF-κB 的活性。此外，miR-892b 的下调归因于其启动子的异常高甲基化。总之，我们的研究结果提供了一种新的机制，即 NF-κB 信号在乳腺癌中持续激活，并提示 miR-892b 具有肿瘤抑制作用，这促使进一步研究 miRNA 模拟物在癌症治疗中的应用。
