MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer.
MicroRNA-574-3p, identified by microRNA library-based functional screening, modulates tamoxifen response in breast cancer.
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DOI：
10.1038/srep07641
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发表时间：
2015-01-06
影响因子：
4.6
通讯作者：
Inoue S
中科院分区：
文献类型：
--
作者：
Ujihira T;Ikeda K;Suzuki T;Yamaga R;Sato W;Horie-Inoue K;Shigekawa T;Osaki A;Saeki T;Okamoto K;Takeda S;Inoue S
大多数原发乳腺癌表达雌激素受体α，可通过使用他莫昔芬等抗雌激素药物进行内分泌治疗；然而，获得性内分泌抵抗是一个关键问题。为了鉴定乳腺癌中的三苯氧胺反应相关的microRNAs(MiRNAs)，将慢病毒miRNA文库感染的MCF-7细胞用4-羟基三苯氧胺(OHT)或赋形剂处理4周，用基因芯片检测整合到基因组中的单个miRNA前体的数量。与赋形剂处理的细胞相比，发现了5个在OHT处理的细胞中下调的“缺失的”miRNAs和6个在OHT处理的细胞中上调的“保留的”miRNAs。在缺失的miRNAs中，我们发现miR-574-3p在临床乳腺癌组织中的表达低于其配对的癌旁组织。此外，抗miR-574-3p可逆转三苯氧胺对MCF-7细胞生长的抑制作用。利用clathrin Heavy Chain(Cltc)基因3‘端非翻译区，通过计算机算法和荧光素酶报告基因分析，确定cltc为miR-574-3p靶基因。有趣的是，在MCF-7细胞中miR-574-3p功能的丧失和获得分别导致Cltc上调和下调。这些结果表明，由miRNA文库介导的功能筛选可以为乳腺癌中他莫昔芬应答所必需的基因提供新的见解。
Most primary breast cancers express estrogen receptor α and can be treated via endocrine therapy using anti-estrogens such as tamoxifen; however, acquired endocrine resistance is a critical issue. To identify tamoxifen response-related microRNAs (miRNAs) in breast cancer, MCF-7 cells infected with a lentiviral miRNA library were treated with 4-hydroxytamoxifen (OHT) or vehicle for 4 weeks, and the amounts of individual miRNA precursors that had integrated into the genome were evaluated by microarray. Compared to the vehicle-treated cells, 5 ‘dropout' miRNAs, which were downregulated in OHT-treated cells, and 6 ‘retained' miRNAs, which were upregulated in OHT-treated cells, were identified. Of the dropout miRNAs, we found that miR-574-3p expression was downregulated in clinical breast cancer tissues as compared with their paired adjacent tissues. In addition, anti-miR-574-3p reversed tamoxifen-mediated suppression of MCF-7 cell growth. Clathrin heavy chain (CLTC) was identified as a miR-574-3p target gene by in silico algorithms and luciferase reporter assay using the 3′ untranslated region of CLTC mRNA. Interestingly, loss and gain of miR-574-3p function in MCF-7 cells causes CLTC to be upregulated and downregulated, respectively. These results suggest that functional screening mediated by miRNA libraries can provide new insights into the genes essential for tamoxifen response in breast cancer.
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