MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells
MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells
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DOI：
10.1158/0008-5472.can-07-2462
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Krueger, Leslie J.
中科院分区：
文献类型：
--
作者：
Sampson, Valerie B.;Rong, Nancy H.;Krueger, Leslie J.
MYC致癌基因的调节尚不清楚。使用10058-F4，一种抑制MYC-MAX转录因子的化合物，MYC蛋白和基因表达在Burkitt淋巴瘤Namalwa细胞中下调。化合物10058-F4降低了MYC mRNA（45％），MYC蛋白（50％）和细胞生长（32％）。治疗后24小时，MYC-MAX转录因子被破坏，从而导致靶基因的转录抑制。因为使用生物信息学用于靶向MYC，选择了microRNA（miRNA）破坏mRNA翻译，let-7a，let-7b和miR-98。以10058-174的抑制Myc-Max转录因子增加了Let-7家族成员的水平。在24 IT的抑制细胞中，Let-7a，Let-7b和miR-98分别诱导4.9-，1.3-和2.4倍，而miR-17-5p降低了0.23倍。使用microRNA多摩菌悬浮阵列技术对这些结果进行了复制。 LET-7A对MYC mRNA的调节已通过前LET-7A的转染证实。 Let-7a的过表达（190％）降低了MYC mRNA（70％）和蛋白质（75％）。使用siRNA MYC对MYC蛋白和mRNA的下调也升高了Let-7a miRNA并降低了MYC基因表达。在10058-174，LET-7A或siRNA MYC之前，LET-7A和MIR-17-5P对MYC mRNA的逆坐标调节表明，这两个miRNA均受myc调节。这支持了肺癌和结肠癌的先前结果，在肺癌和结肠癌中降低了let-7家族水平导致肿瘤性增加。在这里，LET-7A前转染导致MYC及其靶基因表达的下调以及淋巴瘤细胞中的抗增殖。这些带有LET-7A的发现增加了MYC调节的复杂性，并表明这些miRNA失调参与了Burkitt淋巴瘤细胞和其他MyC-dromendroncropenconcropendencropendenconcrodencon的淋巴瘤表型的起源和维持。
Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-174 increased levels of members of the let-7 family. In inhibited cells at 24 It, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-174, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to downregulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers.