Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells.
Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells.
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DOI：
10.1371/journal.pone.0031422
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shimizu K
中科院分区：
文献类型：
--
作者：
Ichikawa T;Sato F;Terasawa K;Tsuchiya S;Toi M;Tsujimoto G;Shimizu K
曲妥珠单抗已用于治疗 HER2 阳性乳腺癌 (BC)。然而，一部分 BC 患者表现出对曲妥珠单抗治疗的耐药性。因此，阐明曲妥珠单抗治疗的分子机制将有利于改善HER2阳性BC患者的治疗。在这项研究中，我们鉴定了与曲妥珠单抗治疗效果相关的曲妥珠单抗反应性 microRNA。 RNA 样本取自接受或未接受曲妥珠单抗治疗 6 天的 HER2 阳性（SKBR3 和 BT474）和 HER2 阴性（MCF7 和 MDA-MB-231）细胞。接下来，我们使用这些样本进行了 microRNA 分析，以筛选那些仅在 HER2 阳性细胞中上调或下调的 microRNA。该分析将 miR-26a 和 miR-30b 鉴定为曲妥珠单抗诱导型 microRNA。转染 miR-26a 和 miR-30b 分别诱导 BC 细胞生长抑制 40% 和 32%。细胞周期分析表明，这些 microRNA 与曲妥珠单抗一样，在 HER2 阳性 BC 细胞中诱导 G1 期停滞。膜联蛋白-V 测定显示，miR-26a 而不是 miR-30b 诱导 HER2 阳性 BC 细胞凋亡。使用 microRNA 靶标的预测算法，我们将细胞周期蛋白 E2 (CCNE2) 确定为 miR-30b 的靶基因。基于荧光素酶的报告分析表明，miR-30b 通过与 CCNE2 3'-UTR 中的两个结合位点相互作用，转录后基因表达降低了 27% (p = 0.005)。在 BC 细胞中，曲妥珠单抗调节一部分 microRNA 的表达，包括 miR-26a 和 miR-30b。曲妥珠单抗对 miR-30b 的上调可能在曲妥珠单抗通过靶向 CCNE2 诱导的细胞生长抑制中发挥生物学作用。
Trastuzumab has been used for the treatment of HER2-positive breast cancer (BC). However, a subset of BC patients exhibited resistance to trastuzumab therapy. Thus, clarifying the molecular mechanism of trastuzumab treatment will be beneficial to improve the treatment of HER2-positive BC patients. In this study, we identified trastuzumab-responsive microRNAs that are involved in the therapeutic effects of trastuzumab. RNA samples were obtained from HER2-positive (SKBR3 and BT474) and HER2-negetive (MCF7 and MDA-MB-231) cells with and without trastuzumab treatment for 6 days. Next, we conducted a microRNA profiling analysis using these samples to screen those microRNAs that were up- or down-regulated only in HER2-positive cells. This analysis identified miR-26a and miR-30b as trastuzumab-inducible microRNAs. Transfecting miR-26a and miR-30b induced cell growth suppression in the BC cells by 40% and 32%, respectively. A cell cycle analysis showed that these microRNAs induced G1 arrest in HER2-positive BC cells as trastuzumab did. An Annexin-V assay revealed that miR-26a but not miR-30b induced apoptosis in HER2-positive BC cells. Using the prediction algorithms for microRNA targets, we identified cyclin E2 (CCNE2) as a target gene of miR-30b. A luciferase-based reporter assay demonstrated that miR-30b post-transcriptionally reduced 27% (p = 0.005) of the gene expression by interacting with two binding sites in the 3′-UTR of CCNE2. In BC cells, trastuzumab modulated the expression of a subset of microRNAs, including miR-26a and miR-30b. The upregulation of miR-30b by trastuzumab may play a biological role in trastuzumab-induced cell growth inhibition by targeting CCNE2.
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影响因子：
4.8
作者：
Miller, Tyler E.;Ghoshal, Kalpana;Majumder, Sarmila
通讯作者：
Majumder, Sarmila
DOI：
10.1056/nejmoa0901282
发表时间：
2009-10-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ji J;Shi J;Budhu A;Yu Z;Forgues M;Roessler S;Ambs S;Chen Y;Meltzer PS;Croce CM;Qin LX;Man K;Lo CM;Lee J;Ng IO;Fan J;Tang ZY;Sun HC;Wang XW
通讯作者：
Wang XW
影响因子：
46.9
作者：
Rozowsky, Joel;Euskirchen, Ghia;Auerbach, Raymond K.;Zhang, Zhengdong D.;Gibson, Theodore;Bjornson, Robert;Carriero, Nicholas;Snyder, Michael;Gerstein, Mark B.
通讯作者：
Gerstein, Mark B.
影响因子：
--
作者：
Davoren, Pamela A.;McNeill, Roisin E.;Lowery, Aoife J.;Kerin, Michael J.;Miller, Nicola
通讯作者：
Miller, Nicola
影响因子：
3.5
作者：
Dubská, L;Andera, L;Sheard, MA
通讯作者：
Sheard, MA