Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22
Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22
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DOI：
10.1038/onc.2010.510
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发表时间：
2011-03-01
期刊：
影响因子：
8
通讯作者：
Nakshatri, H.
中科院分区：
文献类型：
--
作者：
Patel, J. B.;Appaiah, H. N.;Nakshatri, H.
乳腺癌的转移比局部原发疾病的预后更差。为了确定与转移相关的microRNAs(MiRNA)，利用基因芯片分析了下列细胞系中254个miRNAs的表达：MDA-MB-231乳腺癌细胞、裸鼠乳腺脂肪垫肿瘤生长的细胞(TMD-231)、肺转移瘤(LMD-231)、骨(BMD-231)和肾上腺(ADMD-231)。此外，在验证研究中还使用了该细胞系(231-BR)的一个脑部寻找变体。与TMD-231细胞相比，转移癌细胞中有20个miRNAs表达上调，7个miRNAs表达下调。在转移性癌细胞中，肿瘤抑制基因miRNAs let-7和miR-22的表达持续下调。这些转移细胞表达较高水平的假定/已证实的miR-22靶癌基因ERBB3、CDC25C和EVI-1。将miR-22引入癌细胞，降低了ERBB3和EVI-1以及EVI-1下游靶点磷酸化AKT的水平。MiR-22的初级转录本位于开放阅读框C17orf91的50个非翻译区，C17orf91的启动子/增强子驱动miR-22的表达。我们观察到C17orf91在非基本亚型乳腺癌中的表达高于基本亚型乳腺癌。相反，在雌激素受体阴性的乳腺癌患者中，EVI-1的高表达在基础亚型中被观察到，并与不良预后相关。这些结果表明，转移性癌细胞通过下调miRNAs来增加特定的致癌信号蛋白。识别这种转移特异的致癌途径可能有助于操纵肿瘤的行为，并有助于设计更有效的靶向治疗。Oncogene(2011年)30,12901301；doi：10.1038/onc.2010.510；2010年11月8日在线发布
Metastasis in breast cancer carries a disproportionately worse prognosis than localized primary disease. To identify microRNAs (miRNA) involved in metastasis, the expression of 254 miRNAs was measured across the following cell lines using microarray analysis: MDA-MB-231 breast cancer cells, cells that grew as a tumor in the mammary fat pad of nude mice (TMD-231), metastatic disease to the lungs (LMD-231), bone (BMD-231) and adrenal gland (ADMD-231). A brain-seeking variant of this cell line (231-BR) was used additionally in validation studies. Twenty miRNAs were upregulated and seven were downregulated in metastatic cancer cells compared with TMD-231 cells. The expression of the tumor suppressor miRNAs let-7 and miR-22 was consistently downregulated in metastatic cancer cells. These metastatic cells expressed higher levels of putative/proven miR-22 target oncogenes ERBB3, CDC25C and EVI-1. Introduction of miR-22 into cancer cells reduced the levels of ERBB3 and EVI-1 as well as phospho-AKT, an EVI-1 downstream target. The miR-22 primary transcript is located in the 50-untranslated region of an open reading frame C17orf91, and the promoter/enhancer of C17orf91 drives miR-22 expression. We observed elevated C17orf91 expression in non-basal subtype compared with basal subtype breast cancers. In contrast, elevated expression of EVI-1 was observed in basal subtype and was associated with poor outcome in estrogen receptor-negative breast cancer patients. These results suggest that metastatic cancer cells increase specific oncogenic signaling proteins through downregulation of miRNAs. Identifying such metastasis-specific oncogenic pathways may help to manipulate tumor behavior and aid in the design of more effective targeted therapies. Oncogene (2011) 30, 1290-1301; doi:10.1038/onc.2010.510; published online 8 November 2010