Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b
Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b
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DOI：
10.1074/jbc.m609383200
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发表时间：
2007-01-12
影响因子：
4.8
通讯作者：
Benz, Christopher C.
中科院分区：
文献类型：
--
作者：
Scott, Gary K.;Goga, Andrei;Benz, Christopher C.
微RNA（miRNAs）的失调正在成为癌症病因学的一个主要方面，因为它们指导靶向转录物的翻译和稳定性的能力可以显著影响细胞生理学。为了探索外源性应用的miRNA抑制致癌蛋白的潜力，通过生物信息学检索选择ERBB癌基因家族，鉴定ERBB 2和ERBB 3的3 '-非翻译区内miR-125 a和miR-125 b的靶向种子序列。使用人乳腺癌细胞系SKBR 3作为ERBB 2和ERBB 3依赖性的模型，用表达miR-125 a或miR-125 b的逆转录病毒构建体感染这些细胞导致ERBB 2和ERBB 3在转录物和蛋白质水平上的抑制。相对于对照，含有ERBB 2和ERBB 3的3'3'-非翻译区的荧光素酶构建体在表达miR-125 a和miR-125 b的细胞中表现出类似于低35%的活性。此外，ERK 1/2和AKT的磷酸化在过表达miR-125 a或miR-125 b的SKBR 3细胞中受到抑制。与ERBB 2和ERBB 3信号传导的抑制一致，miR-125 a或miR-125 b过表达的SKBR 3细胞的锚定依赖性生长受损，并表现出迁移和侵袭能力降低。对MCF 10A细胞进行的平行研究表明，miR-125 a或miR-125 b过表达对这些非转化的人乳腺上皮细胞的生长和迁移仅产生轻微影响。这些结果说明了使用miRNA作为抑制癌基因表达和功能的治疗策略的可行性。
Deregulation of micro-RNAs (miRNAs) is emerging as a major aspect of cancer etiology because their capacity to direct the translation and stability of targeted transcripts can dramatically influence cellular physiology. To explore the potential of exogenously applied miRNAs to suppress oncogenic proteins, the ERBB oncogene family was chosen with a bioinformatics search identifying targeting seed sequences for miR-125a and miR-125b within the 3'-untranslated regions of both ERBB2 and ERBB3. Using the human breast cancer cell line SKBR3 as a model for ERBB2 and ERBB3 dependence, infection of these cells with retroviral constructs expressing either miR-125a or miR-125b resulted in suppression of ERBB2 and ERBB3 at both the transcript and protein level. Luciferase constructs containing the 3' 3'-untranslated regions of ERBB2 and ERBB3 demonstrated similar to 35% less activity in miR-125a- and miR-125b-expressing cells relative to controls. Additionally, phosphorylation of ERK1/2 and AKT was suppressed in SKBR3 cells overexpressing either miR-125a or miR-125b. Consistent with suppression of both ERBB2 and ERBB3 signaling, miR-125a- or miR-125b-overexpressing SKBR3 cells were impaired in their anchorage-dependent growth and exhibited reduced migration and invasion capacities. Parallel studies performed on MCF10A cells demonstrated that miR-125a or miR- 125b overexpression produced only marginal influences on the growth and migration of these non-transformed human mammary epithelial cells. These results illustrate the feasibility of using miRNAs as a therapeutic strategy to suppress oncogene expression and function.