The miR-17-92 Cluster of MicroRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence

In mammalian cells, activation of oncogenes usually triggers innate tumor-suppressing defense mechanisms including apoptosis and senescence, which are compromised by additional mutations before cancers are developed. The miR-17-92 gene cluster, a polycistron encoding 6 microRNAs (miRNAs), is frequently overexpressed in human cancers, and has been shown to promote several aspects of oncogenic transformation, including evasion of apoptosis. In the current study, we demonstrate a new role of miR-17-92 in inhibiting oncogenic ras-induced senescence. Further dissection of the miRNA components in this cluster reveals that the miR-17/miR-20a seed family accounts for this anti-senescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring resistance to ras-induced senescence, by directly targeting p21WAF1, a key effector of senescence. By contrast, these components are not essential for the ability of miR-17-92 to evade Myc-induced apoptosis. Moreover, disruption of senescence by miR-17-92 or its miR-17/20a components leads to enhanced oncogenic transformation by activated ras in primary human cells. Taken together with previous reports that miR-17-92 inhibits apoptosis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster promotes tumorigenesis by antagonizing both tumor-suppressing mechanisms, apoptosis and senescence, through the activities of different miRNA components encoded in this cluster.