Petrocca Fabio, Visone Rosa, Onelli Mariadele Rapazzotti, Shah Manisha H, Nicoloso Milena S, de Martino Ivana, Iliopoulos Dimitrios, Pilozzi Emanuela, Liu Chang-Gong, Negrini Massimo, Cavazzini Luigi, Volinia Stefano, Alder Hansjuerg, Ruco Luigi P, Baldassarre Gustavo, Croce Carlo M, Vecchione Andrea
Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA.
Cancer Cell. 2008 Mar;13(3):272-86. doi: 10.1016/j.ccr.2008.02.013.
Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.
E2F1活性失调和对转化生长因子β（TGFβ）的抗性是胃癌的标志。微小RNA（miRNA）是在人类恶性肿瘤中经常失调的小非编码RNA。在此，我们提供证据表明，在一部分人类胃肿瘤中上调的miR-106b-25簇，与其宿主基因Mcm7一起被E2F1激活。反过来，miR-106b和miR-93调节E2F1表达，建立了一个miRNA介导的负反馈环。此外，这些miRNA的上调会损害TGFβ肿瘤抑制途径，干扰细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A，即p21（Waf1/Cip1））和BCL2样蛋白11（Bim）的表达。总之，这些结果表明，miR-106b-25簇参与E2F1的转录后调控，并可能在胃癌中TGFβ抗性的发展中起关键作用。
