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微小RNA-1207-5p通过抑制LZTS1的表达来调节三阴性乳腺癌细胞对紫杉醇治疗的敏感性。

miR-1207-5p regulates the sensitivity of triple-negative breast cancer cells to Taxol treatment via the suppression of LZTS1 expression.

作者信息

Hou Xiaoke, Niu Zhaofeng, Liu Leilei, Guo Qiang, Li Haiyang, Yang Xiaojun, Zhang Xia

机构信息

Department of Breast Surgery, Yuncheng Central Hospital, Yuncheng, Shanxi 044000, P.R. China.

The First Department of Oncology, Linfen Central Hospital, Linfen, Shanxi 041000, P.R. China.

出版信息

Oncol Lett. 2019 Jan;17(1):990-998. doi: 10.3892/ol.2018.9687. Epub 2018 Nov 12.

Abstract

Taxol-based chemotherapy is a conventional therapeutic approach for the treatment of triple-negative breast cancer (TNBC). However, the insensitivity of TNBC cells to Taxol greatly limits the anticancer effect of the drug and leads to patient mortality. The present study first evaluated the expression levels of microRNA (miR)-1207-5p in human normal breast epithelial MCF-10A cells and TNBC cell lines (MDA-MB-231, MDA-MB-436 and MDA-MB-453). The results revealed that the highest miR-1207-5p level was in MDA-MB-231, which suggested an oncogenic role of miR-1207-5p in TNBC. Therefore, MDA-MB-231 served as the present study's research model in subsequent experiments. The mRNAs that functioned as tumor suppressor factors for miR-1207-5p were then determined. Leucine zipper tumor suppressor gene 1 (LZTS1), which was predicted by TargetScan 6.2 and was supported by the results of a dual luciferase assay, was identified as a target of miR-1207-5p. AntagomiR-1207-5p increased LZTS1 mRNA and protein expressions, enhanced cell growth arrest and cell apoptosis induced by Taxol in MDA-MB-231 cells. Additionally, it was observed that, when compared with Taxol treatment, the combination of Taxol and antagomiR-1207-5p induced a sharp decrease in B-cell lymphoma 2 (Bcl-2) and phosphorylated-protein kinase B expression accompanied by an increase in the Bcl-2-associated X protein expression. Finally, miR-1207-5p expression was significantly increased, while LZTS1 expression was significantly decreased, in TNBC tissues when compared with normal adjacent tissues, and there was a negative correlation between miR-1207-5p and LZTS1 expression. In addition, there was a notable elevation in the expression of miR-1207-5p and a reduction in the expression of LZTS1 in the Taxol non-responsive TNBC tissues when compared with the Taxol-responsive TNBC tissues. The results of the present study suggested that miR-1207-5p may be a promising predictor of sensitivity towards Taxol in TNBC.

摘要

基于紫杉醇的化疗是治疗三阴性乳腺癌(TNBC)的传统治疗方法。然而,TNBC细胞对紫杉醇的不敏感性极大地限制了该药物的抗癌效果,并导致患者死亡。本研究首先评估了微小RNA(miR)-1207-5p在人正常乳腺上皮MCF-10A细胞和TNBC细胞系(MDA-MB-231、MDA-MB-436和MDA-MB-453)中的表达水平。结果显示,MDA-MB-231中miR-1207-5p水平最高,这表明miR-1207-5p在TNBC中具有致癌作用。因此,MDA-MB-231在后续实验中作为本研究的研究模型。随后确定了作为miR-1207-5p肿瘤抑制因子的mRNA。通过TargetScan 6.2预测并经双荧光素酶测定结果支持的亮氨酸拉链肿瘤抑制基因1(LZTS1)被鉴定为miR-1207-5p的靶标。抗miR-1207-5p增加了MDA-MB-231细胞中LZTS1 mRNA和蛋白表达,增强了紫杉醇诱导的细胞生长停滞和细胞凋亡。此外,观察到,与紫杉醇治疗相比,紫杉醇和抗miR-1207-5p联合使用导致B细胞淋巴瘤2(Bcl-2)和磷酸化蛋白激酶B表达急剧下降,同时Bcl-2相关X蛋白表达增加。最后,与相邻正常组织相比,TNBC组织中miR-1207-5p表达显著增加,而LZTS1表达显著降低,且miR-1207-5p与LZTS1表达呈负相关。此外,与对紫杉醇敏感的TNBC组织相比,对紫杉醇不敏感的TNBC组织中miR-1207-5p表达显著升高,LZTS1表达降低。本研究结果表明,miR-1207-5p可能是TNBC对紫杉醇敏感性的一个有前景的预测指标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1930/6312986/eee9e0c89de2/ol-17-01-0990-g00.jpg

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