MicroRNAs (miRNAs) reduce the stability of target messenger RNAs (mRNAs), thereby affecting various cellular outcomes, including differentiation, proliferation, and apoptosis. In cancer, miRNAs may either promote or inhibit tumor growth. The polycistronic gene miR-17-92 encodes six miRNAs [miR-17, miR-18, miR-19a and b (miR-19), miR-20, and miR-92a] and is overexpressed in lymphomas, in which miR-19 is the oncogenic mediator of the cluster. Olive et al. found that miR-92a antagonized miR-19 by promoting cell death. However, the oncogenic miR-19 was more abundant in lymphomas. Introduction of a retrovirus vector containing the entire miR-17-92 locus accelerated tumor onset in Eμ-myc mice, a Burkitt’s lymphoma model with B cell–specific expression of c-myc. In comparison, tumor onset was more rapid and more aggressive, and survival time was decreased by nearly half in mice overexpressing a construct in which miR-92a was deleted (17-92∆92) or mutated (17-92Mut92). In contrast, mutations in miR-17 or miR-20 did not affect oncogenesis. c-Myc–induced oncogenesis is associated with simultaneous increases in cell proliferation and p53-dependent apoptosis, creating an environment that selects for tumor cells that can repress apoptosis. Eμ-myc/17-92∆92 or Eμ-myc/17-92Mut92 tumors had a high proliferative index but markedly reduced apoptosis compared with either Eμ-myc- or Eμ-myc/17-92–derived tumors, whereas overexpression of miR-92a enhanced apoptosis and proliferation both in premalignant B cells in Eμ-myc mice and in c-Myc–inducible mouse embryonic fibroblasts (R26MER/MER-MEFs). Microarray analysis showed that miR-92 induced the expression of genes associated with both apoptotic and proliferative pathways. In either R26MER/MER-MEFs or primary mouse B cells, miR-92 increased the stability of p53, as well as both mRNA and protein abundance of Arf, a critical mediator in c-Myc–induced, p53-dependent apoptosis. Thus, miR-92a may functionally couple c-Myc–induced proliferation with c-Myc–induced apoptosis. Knockdown of p53 in R26MER/MER-MEFs blocked the ability of miR-92 to induce apoptosis or proapoptotic genes, and various assays determined that miR-92 directly decreased the stability of Fbw7 mRNA ( encoding an E3 ubiquitin ligase), thus decreasing the abundance of Fbw7 and increasing that of multiple Fbw7 targets, including c-Myc. Transcript analysis in Eμ-myc mice and cells from Burkitt’s lymphoma patients showed that, although the abundance of both miR-19 and miR-92 was increased in premalignant and malignant B cells compared with normal splenic B cells, the ratio of miR-19:miR-92 was markedly increased during lymphomagenesis. The findings functionally dissect the components of a complex miRNA cluster in Myc-mediated tumorigenesis. They also present intriguing prospects for dissecting the functional interactions of other miRNA clusters (see Zeitels and Mendell).
V. Olive, E. Sabio, M. J. Bennett, C. S. De Jong, A. Biton, J. C. McGann, S. K. Greaney, N. M. Sodir, A. Y. Zhou, A. Balakrishnan, M. Foth, M. A. Luftig, A. Goga, T. P. Speed, Z. Xuan, G. I. Evan, Y. Wan, A. C. Minella, L. He, A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis. eLife 2, e00822 (2013). [PubMed]
L. R. Zeitels, J. T. Mendell, When 19 is greater than 92. eLife 2, e01514 (2013). [PubMed]