Fig. 4.
miRNAs as oncogenes and/or tumor suppressors: two different looks of the same genes. A miRNA located in a deleted region or down-regulated in a particular human cancer (a tumor suppressor miRNA) can have, in fact, oncogene-like effects if the main targets for that specific cell types are oncogenes. The absence of the miRNA will induce overexpression of the oncogenic targets, the same effect as the target amplification or activation (as was proved for let-7 and RAS in lung cancers). The same miRNA, but in a different cell type, can have as main target a tumor suppressor and therefore its deletion will increase the levels of the suppressor protein, practically protecting from malignant transformation. A miRNA located in an amplified region or overexpressed in a particular human cancer (an oncogene miRNA) can have, in fact, tumor suppressor-like effects if the main targets for that specific cell types are tumor suppressors. The abundance of the miRNA will produce down-regulation of the suppressor targets, the same effect as the loss of heterozygosity directly affecting the target gene. The same miRNA, but in a different cell type, can have as main target an oncogene, and therefore its overexpression will decrease the levels of the oncogenic protein, practically protecting the cell from malignant transformation. To completely define this puzzle, it has to be considered that, depending on cell type, the same miRNAs (as proved for miR-17-5 and miR-20a) can behave as oncogene (as shown in ref. 28) or tumor suppressor (as shown in ref. 29). Furthermore, each miRNA has more than one target, and each target has more than one interacting miRNA in a specific cell type, giving rise to a very complex and intricate regulatory network. The miRNA genes are shown in blue, and the corresponding promoters are shown in orange. For simplicity, only one allele was shown and only a few mRNA–miRNA interactions are represented.