Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer.
Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer.
复制标题
肿瘤抑制子microRNA-206在乳腺癌中对T-box转录因子Tbx3的调控。
DOI：
10.1038/bjc.2016.73
复制
发表时间：
2016-05-10
影响因子：
8.8
通讯作者：
Sweeney C
中科院分区：
文献类型：
--
作者：
Amir S;Simion C;Umeh-Garcia M;Krig S;Moss T;Carraway KL 3rd;Sweeney C
Tbx 3转录因子在乳腺癌中过表达，它与癌症干细胞群的增殖、迁移和调节有关。调节Tbx 3在癌症中表达的机制尚未完全探索。在这项研究中，我们证明了Tbx 3在乳腺癌细胞中受到肿瘤抑制因子miR-206的抑制。使用生物信息学预测程序和荧光素酶报告基因测定来证明miR-206负调控Tbx 3。我们使用miR-206模拟物和抑制剂检测了miR-206对乳腺癌细胞中Tbx 3表达的影响。通过定量逆转录-PCR和免疫印迹检测基因/蛋白表达。通过细胞死亡检测、集落形成、3D-Matrigel和肿瘤球分析研究miR-206和Tbx 3对凋亡、增殖、侵袭和癌症干细胞群体的影响。在这项研究中，我们研究了miR-206对Tbx 3的调控。我们证明了Tbx 3被miR-206直接抑制，并且Tbx 3的这种抑制对于miR-206抑制乳腺肿瘤细胞增殖和侵袭以及减少癌症干细胞群体是必需的。此外，Tbx 3和miR-206表达在人乳腺癌中呈负相关。Kaplan-Meier分析表明，与具有低Tbx 3和高miR-206表达的患者相比，表现出高Tbx 3和低miR-206表达的组合的患者具有较低的存活概率。这些研究揭示了Tbx 3调控的新机制，并确定了肿瘤抑制因子miR-206的新靶点。本研究将Tbx 3确定为肿瘤抑制因子miR-206的新靶点，并表征了miR-206/Tbx 3信号通路，该通路参与乳腺癌细胞中癌症干细胞群的增殖、侵袭和维持。我们的研究结果表明，Tbx 3阳性乳腺癌中miR-206的恢复可以用于治疗益处。
The Tbx3 transcription factor is over-expressed in breast cancer, where it has been implicated in proliferation, migration and regulation of the cancer stem cell population. The mechanisms that regulate Tbx3 expression in cancer have not been fully explored. In this study, we demonstrate that Tbx3 is repressed by the tumour suppressor miR-206 in breast cancer cells. Bioinformatics prediction programmes and luciferase reporter assays were used to demonstrate that miR-206 negatively regulates Tbx3. We examined the impact of miR-206 on Tbx3 expression in breast cancer cells using miR-206 mimic and inhibitor. Gene/protein expression was examined by quantitative reverse-transcription–PCR and immunoblotting. The effects of miR-206 and Tbx3 on apoptosis, proliferation, invasion and cancer stem cell population was investigated by cell-death detection, colony formation, 3D-Matrigel and tumorsphere assays. In this study, we examined the regulation of Tbx3 by miR-206. We demonstrate that Tbx3 is directly repressed by miR-206, and that this repression of Tbx3 is necessary for miR-206 to inhibit breast tumour cell proliferation and invasion, and decrease the cancer stem cell population. Moreover, Tbx3 and miR-206 expression are inversely correlated in human breast cancer. Kaplan–Meier analysis indicates that patients exhibiting a combination of high Tbx3 and low miR-206 expression have a lower probability of survival when compared with patients with low Tbx3 and high miR-206 expression. These studies uncover a novel mechanism of Tbx3 regulation and identify a new target of the tumour suppressor miR-206. The present study identified Tbx3 as a novel target of tumour suppressor miR-206 and characterised the miR-206/Tbx3 signalling pathway, which is involved in proliferation, invasion and maintenance of the cancer stem cell population in breast cancer cells. Our results suggest that restoration of miR-206 in Tbx3-positive breast cancer could be exploited for therapeutic benefit.