Zhao Yiling, Yang Fenghua, Li Wenyuan, Xu Chunyan, Li Li, Chen Lifei, Liu Yancui, Sun Ping
1 Department of Ultrasound, The Affiliated Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China.
2 Department of Prevention and Health Statistics, Mudanjiang Medical University, Mudanjiang, China.
Tumour Biol. 2017 Feb;39(2):1010428317692264. doi: 10.1177/1010428317692264.
Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to influence the growth of MCF-7 cell.
肿瘤坏死因子受体1是介导许多肿瘤坏死因子-α诱导的细胞事件的主要受体。一些研究表明，肿瘤坏死因子受体1通过激活核因子-κB信号通路促进肿瘤发生，而其他研究证实，肿瘤坏死因子受体1通过诱导乳腺癌细胞凋亡对肿瘤生长起抑制作用。因此，肿瘤坏死因子受体1在乳腺癌中的功能需要阐明。在本研究中，我们首先发现肿瘤坏死因子受体1在人乳腺癌组织和细胞系中显著升高，通过小干扰RNA敲低肿瘤坏死因子受体1可通过阻滞细胞周期和诱导凋亡抑制细胞增殖。此外，通过TargetScan预测miR-29a是肿瘤坏死因子受体1的调节因子，并且在人乳腺癌组织和细胞系中miR-29a与肿瘤坏死因子受体1的表达呈负相关。荧光素酶报告基因检测进一步证实，miR-29a通过与3'非翻译区结合负向调节肿瘤坏死因子受体1的表达。在我们的功能研究中，miR-29a过表达显著抑制MCF-7细胞的增殖和集落形成，阻滞细胞周期，并诱导其凋亡。此外，与肿瘤坏死因子受体1转染联合时，miR-29a显著逆转了肿瘤坏死因子受体1在MCF-7细胞中引起的致癌作用。另外，我们证明miR-29a通过使核因子-κB信号通路失活以及降低细胞周期蛋白D1和Bcl-2/Bax蛋白水平来抑制MCF-7细胞生长。综上所述，我们的结果表明，miR-29a是乳腺癌中肿瘤坏死因子受体1表达的重要调节因子，通过靶向肿瘤坏死因子受体1发挥肿瘤抑制作用，影响MCF-7细胞的生长。
