title: The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence.
abstract: 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 six microRNAs (miRNA), 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 show 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-17/20a seed family accounts for this antisenescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring resistance to ras-induced senescence by directly targeting p21(WAF1), 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.
authors.affiliation: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Hong
authors.forename: Maoyi
authors.initials: M
authors.lastname: Lai
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Changchuan
authors.initials: C
authors.lastname: Xie
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.forename: Changchun
authors.initials: C
authors.lastname: Xiao
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Hu
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003114:Colony-Forming Units Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology / Q000473:pathology*; D009857:Oncogenes / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; D012333:RNA, Messenger; D018631:ras Proteins