MicroRNAs are small (20 to 25 nucleotides) RNA molecules that inhibit gene expression by targeting the messenger RNAs and either inhibiting translation or promoting degradation of the mRNA (see Meltzer). Not only are these small but numerous microRNAs involved in normal gene regulation during cell proliferation and differentiation, they are also implicated in cancer. Three groups provide new insight into the roles of microRNAs in this complex disease. Lu et al. systematically analyzed the abundance and identity of microRNAs in hundreds of human tissue and cancer samples using a new technique based on complementary oligonucleotides coupled to beads carrying fluorescent dyes. They found that the microRNA profiles were effective in classifying tumors based on their developmental history. For example, epithelial samples of the gastrointestinal tract all showed a similar profile, which may reflect their common origin from cells of the embryonic endoderm. In addition, cancer cells had lower abundance of microRNAs when compared with normal cells, which may provide an effective test for classifying samples as normal or tumorigenic diagnostically.
He et al. analyzed an amplified region of chromosome 13 that is associated with some types of B cell lymphoma. The amplified region includes the expressed region c13orf25, which encodes the microRNA cluster mir-17-92. Increased expression of the transcripts from the mir-17-02 cluster was observed in B cell lymphoma samples compared with that in normal samples or samples from tumors that did not have the amplified region (colorectal carcinomas). To directly test whether overexpression of the microRNAs in the mir-17-92 cluster contributed to cancer progression, the authors introduced hematopoetic stem cells engineered to overexpress the oncogene myc, or myc plus a portion of the mir-17-92 cluster, into recipient mice. Latency to lymphoma development was substantially decreased, and penetrance was 100% for lymphoma development in the mice receiving the cells with the microRNA cluster.
O'Donnell et al. revealed an explicit connection between c-Myc and cancer. Using cells in which c-myc could be inducibly expressed, the authors showed that six microRNAs were up-regulated when c-Myc was increased. The six microRNAs were encoded by the mir-17 cluster (which was also the subject of the He et al. report), the mir-106a cluster, and the mir-106b cluster. Cells deficient for Myc showed decreased abundance of the mir-17 microRNAs, and wild-type levels were restored by reconstitution of c-Myc. Chromatin immunoprecipitation analysis indicated that c-Myc bound directly to the mir-17 locus. The transcription factor E2F1 is a target of two of the microRNAs encoded by mir-17, and the gene encoding E2F1 is also a target of c-Myc. The regulation of E2F1 by the microRNAs was confirmed using antisense oligonucleotides to the microRNAs, which increased the abundance of E2F1, and by overexpression of the mir-17 cluster, which decreased E2F1 abundance. In cells induced to overexpress c-Myc, which also induced the microRNAs, E2F1 mRNA was markedly increased (~7 times that in low c-Myc cells); unexpectedly, the abundance of the E2F1 protein showed a smaller increase (1.5 times that in low c-Myc cells). One possible explanation is that the coordinated induction by c-Myc of E2F1 (a positive regulator of the cell cycle) and the microRNAs that inhibit E2F1 translation allows fine-tuning of the system. This may prevent the formation of a runaway positive feedback loop whereby c-Myc increases E2F1 abundance, which in turn increases c-Myc abundance, leading to uncontrollable cell proliferation.
P. S. Meltzer, Cancer genomics: Small RNAs with big impacts. Nature 435, 745-746 (2005). [PubMed]
J. Lu, G. Getz, E. A. Miska, E. Alvarez-Saavedra, J. Lamb, D. Peck, A. Sweet-Cordero, B. L. Ebert, R. H. Mak, A. A. Ferrando, J. R. Downing, T. Jacks, H. R. Horvitz, T. R. Golub, MicroRNA expression profiles classify human cancers. Nature 435, 834-838 (2005). [PubMed]
L. He, J. M. Thomson, M. T. Hemann, E. Hernando-Monge, D. Mu, S. Goodson, S. Powers, C. Cordon-Cardo, S. W. Lowe, G. J. Hannon, S. M. Hammond, A microRNA polycistron as a potential human oncogene. Nature 435, 828-833 (2005). [PubMed]
K. A. O'Donnell, E. A. Wentzel, K. I. Zeller, C. V. Dang, J. T. Mendell, c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839-843 (2005). [PubMed]