Espinosa and Slack: The Role of MicroRNAs in Cancer 135 found to be overexpressed in B-cell lym- phomas [52,53]. The understanding of how BIC might mediate its effects was limited for several years, as it remained unclear how a presumably non-protein-coding RNA with little overall conservation among avian, murine, and human genomes could consis- tently produce lymphomas and induce the overexpression of MYC. Metzler et al. ana- lyzed the phylogenetically conserved re- gions in BIC and found that the highest homology was located in a 138 nucleotide section of the gene, which in fact encoded the pri-miRNA for miR-155 [54]. Subse- quent studies showed that miR-155 expres- sion is upregulated 100-fold in pediatric Burkitt lymphoma, as well as in Hodgkin’s lymphoma and primary mediastinal and cer- tain subsets of large-B cell lymphomas [55, 56,56]. The role of miR-155 is not restricted to B cell lymphomas, however. Recent stud- ies have reported that miR-155 is upregu- lated in breast, lung, colon, and thyroid cancers [57-59]. It has also been reported that mice overexpressing miR-155 under the control of the Eµ enhancer rapidly develop B-cell malignancy, underscoring the ability of miR-155 to induce lymphomagenesis without the requirement for other major ge- netic changes, strongly suggesting miR-155 can act as a bona fide oncogene [60]. Never- theless, the mechanism of action of miR-155 is unknown, stressing the need for further study of this miRNA. The interaction with MYC is not exclu- sive to miR-155. Recent studies have de- scribed the relationship between MYC, cancer, and the 13q31 locus [61,62]. This ge- nomic locus is amplified in a number of can- cers, such as diffuse large-B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and primary cutaneous B-cell lymphoma. However, the only gene overexpressed in this amplicon is a non-protein-coding RNA, C13orf25 [63], which has been shown to en- code the miR-17-92 cluster, containing seven miRNAs: miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92- 1. He et al. have shown that cell lines carrying an amplification of 13q31 were analyzed, and it was found that six miRNAs had increased expression, five of which belonged to the miR-17-92 cluster [61]. Furthermore, it was also shown that the pri-miRNA for the miR-17-92 cluster was upregulated in 65 per- cent of the tested B cell lymphoma samples. These data suggested a direct involvement of this miRNA cluster in tumorigenesis. Further indication of the involvement of the miR-17-92 cluster in cancer was found in subsequent experiments, in which the miR-17-19b-1 cluster (the vertebrate-spe- cific segment of the miR-17-92 cluster) was overexpressed using a retroviral system in hematopoietic stem cells (HSCs) from mice carrying the Myc transgene. Lethally irradi- ated animals which received HSCs express- ing both miR-17-19b-1 cluster and Myc developed malignant lymphomas more rap- idly than those receiving HSCs expressing Myc alone. The lymphomas from mice ex- pressing both Myc and miR-17-19b-1 were characterized by increased cell proliferation and decreased apoptosis levels, when com- pared to the malignancies arising from the mice receiving HSCs with Myc alone. Com- plementary experiments showed that this ef- fect is exclusive to the miRNAs of the miR-17-19b-1 cluster and any one individual miRNA from this cluster is unable to cause accelerated lymphomagenesis. Together, these results suggest that the miRNAs com- posing the miR-17-19b-1 act cooperatively as oncogenes, presumably by targeting proapoptotic and anti-proliferative factors. Independently, O’Donnell et al. identi- fied the miR-17-92 cluster as a group of po- tentially cancer-related genes through microarray analysis of a set of human, mouse, and rat miRNAs to identify miRNAs with altered levels in a human B-cell line that overexpresses MYC [62]. It was found that MYC induced the expression of the miR-17-92 cluster. Moreover, chromatin im- munoprecipitation experiments confirm this interaction by establishing that MYC binds within the first intronic region of C13orf25, suggesting that MYC has the ability to di- rectly regulate the miR-17-92 cluster. An intriguing scenario was suggested by the bioinformatic prediction that the members of the miR-17-92 cluster, miR-17-