Molecular Medicine Select

Small noncoding RNAs, including endogenous antisense RNAs and microRNAs, are involved in many different cellular processes. This issue's Molecular Medicine Select highlights recent work investigating the roles of these RNAs in various aspects of tumorigenesis, suggesting new prognostic, and possibly therapeutic, tools for treating cancer. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. While oncogenic and tumor suppressor roles have been ascribed to some individual miRNAs, global changes in miRNA expression is commonly found in tumor cells. How do miRNAs become dysregulated in tumors? Myc is a well-known oncogene that is activated in many human tumors. Myc can either activate or repress gene expression by directly binding to DNA or inhibiting positive transcription activators, respectively. Myc is known to activate transcription of a cluster of miRNAs that is amplified in lymphoma and solid tumors. Using microarray analysis, Chang et al. (2008) now report a larger set of Myc-regulated miRNAs, the majority of which are downregulated in Myc-inducible human and mouse B cell lymphoma lines. In addition to the previously reported upregulated miRNAs, the authors note increased expression of one other miRNA, miR-7, and decreased expression of 13 miRNAs in the Myc-inducible lymphoma lines. Of the latter, 7 miRNAs are located in chromosomal regions known to be deleted in cancer. A combination of chromatin immunoprecipitation (ChIP) and real-time PCR showed that Myc does bind to at least one transcription start site for each of the 13 Myc-repressed miRNAs. But is decreased expression of these miRNAs important in Myc-mediated tumorigenesis in vivo? Myc-and v-Abl-transformed B cells expressing five of the Myc-repressed miRNAs, when injected into immunodeficient mice, did not contribute to tumor expansion. Meanwhile, miR-26a only decreased tumorigenesis in Myc-transformed cells, and miR-22 only affected tumorigenesis in v-Abl-transformed cells. The mechanism by which these miRNAs inhibit tumorigenesis remains to be elucidated. Together these data implicate the Myc oncogene in the repression of miRNAs that possess antitumorigenic properties. They also support the notion that the widespread downregulation of miRNAs seen in cancer promotes tumorigenesis and is not merely a side effect of transformation. It turns out that miRNAs may regulate not only cancer cell invasiveness (direct migration and penetration by cancer cells into neighboring tissues) but also tumor metastasis (the process of cancer cells leaving the site of origin and migrating to other locations). Huang et al. (2008) performed a genetic screen to identify miRNAs that induce a nonmetastatic human …