Knockdown of Long Non-Coding RNA UCA1 Increases the Tamoxifen Sensitivity of Breast Cancer Cells through Inhibition of Wnt/β-Catenin Pathway.
Knockdown of Long Non-Coding RNA UCA1 Increases the Tamoxifen Sensitivity of Breast Cancer Cells through Inhibition of Wnt/β-Catenin Pathway.
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DOI：
10.1371/journal.pone.0168406
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Liu H;Wang G;Yang L;Qu J;Yang Z;Zhou X
对他莫昔芬的获得性耐药仍然是乳腺癌（BC）治疗的主要障碍，因为其潜在机制尚未完全阐明。尿路上皮癌相关长链非编码RNA（lncRNA）1（UCA 1）最近被证明是失调的，并在乳腺癌的进展中发挥重要作用。本研究旨在探讨UCA 1在BC耐药中的生物学作用及临床意义。因此，我们使用定量PCR检测来评估UCA 1在BC患者组织中的表达，以及体外建立的他莫昔芬耐药BC细胞系。分别采用MTT法、transwell法和流式细胞术检测MCF-7和T47 D细胞的存活率、侵袭能力和凋亡率。通过体内小鼠异种移植模型监测UCA 1对肿瘤发生的影响。分别采用免疫荧光法、western blot法和荧光素酶报告基因法检测Wnt/β-catenin信号通路的激活情况。UCA 1的表达与乳腺癌患者的病理分级和死亡率呈正相关，并且UCA 1在三苯氧胺耐药细胞系中的表达较野生型亲本细胞显著增加。UCA 1的异位表达促进了细胞存活和对他莫昔芬治疗的抗性，而UCA 1的抑制增强了BC细胞对他莫昔芬的敏感性并诱导了更多的凋亡细胞。此外，与亲本MCF-7和T47 D细胞相比，他莫昔芬耐药细胞表现出增加的Wnt信号传导激活，如通过TOP/FOP Wnt荧光素酶报告基因测定和β-连环蛋白蛋白水平所测量的。与这些数据一致，UCA 1消耗减弱了Wnt/β-连环蛋白途径活化的活性和他莫昔芬抗性BC细胞的致瘤性。综上所述，我们的数据突出了UCA 1-Wnt/β-catenin信号通路在乳腺癌三苯氧胺耐药中的关键作用，这可能是有针对性的，以提高乳腺癌三苯氧胺治疗的有效性和疗效。
Acquired resistance to tamoxifen remains a major obstacle in breast cancer (BC) treatment, since the underlying mechanism has not been fully elucidated. The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated and plays important roles in progression of breast cancer. In the present study, we aimed to investigate the biological role and clinical significance of UCA1 in BC drug resistance. Hence, we used quantitative PCR assay to evaluate the UCA1 expression in tissues from patients with BC as well as established tamoxifen-resistant BC cell lines in vitro. We tested the viability, invasive ability and apoptosis rate in MCF-7 and T47D cells using MTT assay, transwell assay and flow cytometry assay, respectively. The influence of UCA1 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/β-catenin signaling pathway was evaluated by immunofluorescence assay, western blot assay and luciferase reporter assay, respectively. We found that the expression of UCA1 positively correlated with the pathological grade and mortality of breast cancer patients, moreover, expressions of UCA1 was increased significantly in the tamoxifen-resistant cell lines compared with the wild type parental cells. Ectopic expression of UCA1 promoted cell survival and resistance to tamoxifen treatment, whereas inhibition of UCA1 enhanced tamoxifen sensitivity of BC cells and induced more apoptotic cells. In addition, tamoxifen-resistant cells exhibited increased Wnt signaling activation as measured by the TOP/FOP Wnt luciferase reporter assay and β-catenin protein level compared with parental MCF-7 and T47D cells, respectively. In line with these data, UCA1 depletion attenuated the activity of Wnt/β-catenin pathway activation and the tumorigenicity of the tamoxifen-resistant BC cells. Taken together, our data highlights the pivotal role of UCA1-Wnt/β-catenin signaling pathway in the tamoxifen resistance in breast cancer, which could be targeted to improve the effectiveness and efficacy of tamoxifen treatment in breast cancer.
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影响因子：
4.8
作者：
Mahmoodzadeh, Shokoufeh;Eder, Sarah;Regitz-Zagrosek, Vera
通讯作者：
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DOI：
10.1016/j.bbagrm.2015.06.003
发表时间：
2016-01
期刊：
Biochimica et biophysica acta
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