Synergistic action of the microRNA-17 polycistron and Myc in aggressive cancer development
Synergistic action of the microRNA-17 polycistron and Myc in aggressive cancer development
复制标题
DOI：
10.1111/j.1349-7006.2007.00531.x
复制
发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Seto, Masao
中科院分区：
文献类型：
--
作者：
Tagawa, Hiroyuki;Karube, Kennosuke;Seto, Masao
在恶性淋巴瘤中负责13q31-q32扩增的c13orf25/miR-17簇含有microRNA-17-18-19-20-92多顺反子。先前的一项研究表明，在将microRNA17-19b移植到EU-myc小鼠体内后，这种多顺反子可以调节肿瘤的形成。另一项研究报道，Myc可以通过直接结合miR-17基因的上游而上调miR-17簇。这些发现表明，Myc和miR-17簇对癌症的发展具有协同作用。在这项研究中，我们观察了47例MYC重排淋巴瘤中的11例复发的13q31-32扩增。C13orf25在MYC重排淋巴瘤中的实时定量聚合酶链式反应分析显示，13q31-32扩增的病例中c13orf25的表达明显高于未扩增的病例，但未扩增的病例中c13orf25的表达仍略有上调。为了研究Myc和miR-17多顺反子在肿瘤发生中的关系，我们用基因工程方法使大鼠成纤维细胞表达miR-17多顺反子(MiR)、Myc或同时表达miR和Myc。在同时转导miR和Myc的大鼠-1细胞中，miR的表达水平最高，而Myc单独转染组的miR表达也略有上调。此外，我们还发现，裸鼠注射同时携带miR和Myc基因的大鼠肿瘤细胞比注射Myc基因细胞的裸鼠有更快的肿瘤生长。这些结果表明，在Myc结构性表达存在的情况下，miR稳定上调，并且miR和Myc的解除调控可能通过抑制肿瘤抑制基因而协同促进侵袭性癌症的发展。
The c13orf25/miR-17 cluster, which is responsible for 13q31-q32 amplification in malignant lymphoma, contains the microRNA-17-18-19-20-92 polycistron. A previous study demonstrated that this polycistron could modulate tumor formation following transplantation of microRNA 17-19b into Eu-myc mice. Another study reported that Myc can upregulate the miR-17 cluster by binding directly upstream of the miR-17 locus. These findings suggest that Myc and the miR-17 cluster synergistically contribute to cancer development. In the study presented here, we observed recurrent 13q31-32 amplification in MYC-rearranged lymphomas (11 of 47 cases). Quantitative real-time polymerase chain reaction analysis of c13orf25 for MYC-rearranged lymphomas demonstrated that cases with 13q31-32 amplification showed significantly higher expression of c13orf25 than cases without such amplification, although cases without 13q31-32 amplification still showed slight upregulation of c13orf25. To investigate the relationship between Myc and the miR-17 polycistron in tumorigenesis, we engineered rat fibroblasts (Rat-1) that constitutively express the miR-17 polycistron (miR), Myc, or both miR and Myc. The highest level of miR expression was detected in Rat-1 transfected with both miR and Myc, whereas Myc transfectant cells alone also showed slight upregulation of miR. Furthermore, we demonstrated that nude mice injected with Rat-1 transfected with both miR and Myc presented more accelerated tumor growth than those injected with Myc transfectant cells. These results suggest that miR is stably upregulated in the presence of constitutive expression of Myc, and that the deregulation of miR and Myc synergistically contribute to aggressive cancer development, probably by repressing tumor suppressor genes.