Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran.
Department of Medical Biotechnology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran.
Toxicol Appl Pharmacol. 2023 Sep 15;475:116652. doi: 10.1016/j.taap.2023.116652. Epub 2023 Aug 7.
Recently, miRNAs have been regarded as potential candidates for mediating therapeutic functions by targeting genes related to drug response. In this study, we suggested that plasma miRNAs may be correlated with response to trastuzumab in HER2-positive breast cancer patients. To determine whether miR-195, miR-23b-3p, miR-1246, and miR-34c-3p are involved in trastuzumab resistance, we screened their expressions in the BT-474 cell line, which was followed by plasma analysis from 20 trastuzumab-resistant HER2-positive breast cancer patients and 20 nonresistance subjects. Then, TargetScan, Pictar, and miRDB were applied to find the possible targets of the selected miRNAs. In addition, the expression status of admitted targets was evaluated. Our results showed that in resistant BT-474 cells, miR-1246, and miR-23b-3p were significantly upregulated, and miR-195-5p and miR-34c-3p were downregulated. In plasma analysis, we found miR-195-5p, miR-34c-3p, and miR-1246 meaningfully diminished in the resistant group, while the expression of miR-23b-3p was not statistically different. The expression levels of confirmed targets by qRT-PCR showed that the expression of RAF1, AKT3, c-MET, CCND1, PHLPP2, MYB, MAP2K1, and PTEN was significantly upregulated, while the expression of CCNG2 was significantly downregulated. The networks of miRNAs with their confirmed targets improved comprehension of miRNA-mediated therapeutic responses to trastuzumab and might be proposed for more characterization of miRNA functions. Moreover, these data indicated that miR-195-5p, miR-34c-3p, and miR-1246 could be possible biomarkers for prognosis and early detection of the trastuzumab-resistant group from the sensitive group of HER2-positive breast cancer patients.
最近，miRNAs 被认为是通过靶向与药物反应相关的基因来介导治疗作用的潜在候选物。在这项研究中，我们提出血浆 miRNAs 可能与曲妥珠单抗治疗 HER2 阳性乳腺癌患者的反应相关。为了确定 miR-195、miR-23b-3p、miR-1246 和 miR-34c-3p 是否参与曲妥珠单抗耐药，我们筛选了 BT-474 细胞系中的表达，随后对 20 例曲妥珠单抗耐药的 HER2 阳性乳腺癌患者和 20 例非耐药患者的血浆进行了分析。然后，应用 TargetScan、Pictar 和 miRDB 寻找选定 miRNA 的可能靶点。此外，还评估了被认可的靶基因的表达状态。我们的研究结果表明，在耐药的 BT-474 细胞中，miR-1246 和 miR-23b-3p 显著上调，而 miR-195-5p 和 miR-34c-3p 下调。在血浆分析中，我们发现耐药组中 miR-195-5p、miR-34c-3p 和 miR-1246 显著减少，而 miR-23b-3p 的表达没有统计学差异。qRT-PCR 证实的靶基因表达水平表明，RAF1、AKT3、c-MET、CCND1、PHLPP2、MYB、MAP2K1 和 PTEN 的表达显著上调，而 CCNG2 的表达显著下调。miRNA 与其确认靶基因的网络提高了对 miRNA 介导的曲妥珠单抗治疗反应的理解，可能有助于更全面地描述 miRNA 功能。此外，这些数据表明 miR-195-5p、miR-34c-3p 和 miR-1246 可能是预测和早期检测 HER2 阳性乳腺癌患者曲妥珠单抗耐药组的预后和早期检测的潜在生物标志物。
