Sha L-Y, Zhang Y, Wang W, Sui X, Liu S-K, Wang T, Zhang H
Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Eur Rev Med Pharmacol Sci. 2016 Jun;20(11):2201-8.
MiR-18a is a miRNA that is aberrantly overexpressed in triple-negative breast cancer (TNBC). However, its biophysical function in TNBC is still not clear. In this study, we investigated the association among miR-18a dysregulation, Dicer dysregulation and paclitaxel (PTX) resistance in TNBC cells.
20 TNBC patients who received neoadjuvant chemotherapy before surgery were recruited. MiR-18a expression was quantified using QRT-PCR. The effects of miR-18a overexpression or knockdown on cell viability and apoptosis of PTX sensitive MDA-MB-231 cells and PTX resistant MDA-MB-231 cells after PTX treatment were studied. The influence of miR-18a overexpression on Dicer expression was measured by qRT-PCR and Western blot analysis.
Tissues from patients with stable disease (SD, n = 5) and progressive disease (PD, n = 2) to paclitaxel (PTX) containing neoadjuvant chemotherapy had significantly higher miR-18a expression than that from patients with partial response (PR, n = 13). MDA-MB-231/PTX cells had higher miR-18a expression than MDA-MB-231 cells. MiR-18a overexpression directly led to Dicer repression at mRNA and protein level. MiR-18a overexpression significantly increased PTX IC50 and reduced PTX induced cell apoptosis, while miR-18a suppression substantially decreased PTX IC50 and increased PTX induced cell apoptosis.
This study found that miR-18a is an important miRNA that suppresses Dicer expression and increases PTX resistance in TNBC cells.
MiR-18a是一种在三阴性乳腺癌（TNBC）中异常高表达的微小RNA。然而，其在TNBC中的生物物理功能仍不清楚。在本研究中，我们调查了TNBC细胞中MiR-18a失调、Dicer失调与紫杉醇（PTX）耐药性之间的关联。
招募20例术前接受新辅助化疗的TNBC患者。使用QRT-PCR对MiR-18a表达进行定量。研究了MiR-18a过表达或敲低对PTX处理后PTX敏感的MDA-MB-231细胞和PTX耐药的MDA-MB-231细胞活力和凋亡的影响。通过qRT-PCR和蛋白质印迹分析测量MiR-18a过表达对Dicer表达的影响。
对含紫杉醇（PTX）的新辅助化疗病情稳定（SD，n = 5）和病情进展（PD，n = 2）的患者组织中MiR-18a表达明显高于部分缓解（PR，n = 13）的患者。MDA-MB-231/PTX细胞中MiR-18a表达高于MDA-MB-231细胞。MiR-18a过表达直接导致Dicer在mRNA和蛋白质水平受到抑制。MiR-18a过表达显著增加PTX的半数抑制浓度（IC50）并减少PTX诱导的细胞凋亡，而抑制MiR-18a则大幅降低PTX的IC50并增加PTX诱导的细胞凋亡。
本研究发现MiR-18a是一种重要的微小RNA，可抑制TNBC细胞中Dicer的表达并增加PTX耐药性。
