Previous evidence has implied that microRNAs (miRNAs) are involved in tumorigenesis. Two papers published recently in Nature now confirm this, but from different perspectives — a specific cluster of miRNAs (mir-17) on chromosome 13 have the potential to function either as tumour-suppressor genes or as oncogenes.

miRNAs are short RNA molecules that are initially transcribed as long primary transcripts (pri-miRNA) that are processed to make mature miRNAs. They regulate the stability or translational efficiency of their target mRNAs and can be involved in the regulation of differentiation, proliferation or apoptosis.

As the transcription factor MYC is also involved in regulating proliferation and apoptosis, and is involved in tumorigenesis, Joshua Mendell and colleagues asked if any miRNAs are MYC regulated. They used a spotted oligonucleotide array of 235 miRNAs to analyse MYC-dependent miRNA expression in a human B-cell line expressing a tetracycline-responsive MYC transgene. Six miRNAs were upregulated in the MYC-overexpressing cells and these corresponded to transcripts from the mir-17 cluster. After verifying that MYC also upregulates a subset of these miRNAs in rat fibroblasts, the authors addressed whether MYC binds to the mir-17 locus. Seven putative MYC-binding sites were found and MYC was shown to bind an atypical MYC consensus sequence within intron 1 of the mir-17 cluster primary transcript.

What does this mean in terms of cellular function? MYC regulates the expression of the transcription factor E2F1, which, in turn, can further upregulate MYC expression in a putative feed-forward loop. E2F1 is predicted to be regulated by this subset of miRNAs and the authors showed that mir-17 miRNA expression decreased, but did not completely suppress, the levels of E2F1 protein. They suggest that the miRNAs control MYC-induced proliferation by inhibiting the overproduction of E2F1. These miRNAs might potentially function as tumour-suppressor genes. However, as overproduction of E2F1 is also known to cause apoptosis, the mir-17 cluster might promote tumorigenesis by preventing E2F1-induced cell death.

Scott Hammond and colleagues also examined the mir-17 cluster, but from a different viewpoint. A region of chromosome 13 that includes this cluster is amplified in a range of human B-cell lymphomas. The authors established that the pri-miRNAs from this cluster were upregulated in 65% of the human B-cell lymphomas that they tested, whereas this was rarely the case in a panel of human colorectal cancers. To assess the function of these mir-17 miRNAs in B-cell lymphoma, the authors constructed a murine-stem-cell retrovirus that expressed the vertebrate-specific miRNAs. They then compared lymphoma development in irradiated mice injected with haemopoietic stem cells (HSCs) that overexpressed MYC and were infected with either the wild-type or the miRNA-expressing retrovirus. In the absence of miRNA expression and because of the deregulated expression of MYC some, but not all, of the mice developed lymphoma. However, all of the mice that received the HSCs expressing the miRNAs as well as MYC rapidly developed aggressive lymphoma. These lymphomas consisted of pre-B cells, unlike the MYC-induced lymphomas, and showed significantly reduced levels of apoptosis — apoptosis being normally evident in MYC-driven lymphomas. Given that these miRNAs are also expressed in embryonic stem cells the authors propose that expression of these miRNAs might confer a stem-cell-like phenotype. This, combined with a reduction in apoptosis implies that the mir-17 miRNAs have oncogenic potential in this context.

As miRNAs affect the regulation of a range of mRNAs, many of which have yet to be characterized, no doubt the genetics and microenvironment of the cell, and other factors, will influence the effect of these miRNAs in tumorigenesis. More work will undoubtedly follow.