miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells
miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells
复制标题
miR-15b和miR-16通过靶向人胃癌细胞中的BCL2调节多药耐药性
DOI：
10.1002/ijc.23501
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发表时间：
2008-07-15
影响因子：
6.4
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Xia, Lin;Zhang, Dexin;Fan, Daiming
MicroRNAs是一种内源性非编码小RNA，在转录后水平负向调节基因表达。这一复杂的基因调控电路的最新补充彻底改变了我们理解人体生理和病理过程的方式。在这里，我们研究了microRNAs在胃癌细胞多药耐药(MDR)发展中的可能作用。MicroRNA表达谱显示，与其亲本SGC7901细胞株相比，耐多药胃癌细胞株SGC7901/VCR中有一组表达发生变化的有限的microRNA。下调的microRNAs包括miR-15/16家族成员miR-15b和miR-16，qRT-PCR进一步证实了它们的表达。体外药敏实验表明，miR-15b或miR-16过表达可使SGC7901/VCR细胞对抗癌药物增敏，而反义寡核苷酸可抑制它们的表达，使SGC7901细胞产生多药耐药。在SGC7901/VCR细胞中，miR-15b和miR-16表达下调的同时，Bcl2蛋白表达上调。在SGC7901/VCR细胞中，增强的mir-15b或miR-16表达降低了BCL2蛋白水平和BCL2 3‘非翻译区报告结构的荧光素酶活性，表明BCL2是miR-15b和miR-16的直接靶点。此外，miR-15b或miR-16的过表达可使SGC7901/VCR细胞对VCR诱导的细胞凋亡敏感。综上所述，我们的研究结果提示miR-15b和miR-16可能至少部分通过靶向bcl2调控细胞凋亡而在胃癌细胞多药耐药的发生发展中发挥作用。(C)2008年Wiley-Liss，Inc.
microRNAs are endogenous small noncoding RNAs that regulate gene expression negatively at posttranscriptional level. This latest addition to the complex gene regulatory circuitry revolutionizes our way to understanding physiological and pathological processes in the human body. Here we investigated the possible role of microRNAs in the development of multidrug resistance (MDR) in gastric cancer cells. microRNA expression profiling revealed a limited set of microRNAs with altered expression in multidrug-resistant gastric cancer cell line SGC7901/VCR compared to its parental SGC7901 cell line. Among the downregulated microRNAs are miR-15b and miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR. In vitro drug sensitivity assay demonstrated that overexpression of miR-15b or miR-16 sensitized SGC7901/VCR cells to anticancer drugs whereas inhibition of them using antisense oligonucleotides conferred SGC7901 cells MDR. The downregulation of miR-15b and miR-16 in SGC7901/VCR cells was concurrent with the upregulation of Bcl-2 protein. Enforced mir-15b or miR-16 expression reduced Bcl-2 protein level and the luciferase activity of a BCL2 3' untranslated region-based reporter construct in SGC7901/VCR cells, suggesting that BCL2 is a direct target of miR-15b and miR-16. Moreover, overexpression of miR-15b or miR-16 could sensitize SGC7901/VCR cells to VCR-induced apoptosis. Taken together, our findings suggest that miR-15b and miR-16 could play a role in the development of MDR in gastric cancer cells at least in part by modulation of apoptosis via targeting BCL2. (C) 2008 Wiley-Liss, Inc.