title: The oncogenic microRNA-21 inhibits the tumor suppressive activity of FBXO11 to promote tumorigenesis.
abstract: The microRNA miR-21 is overexpressed in most human cancers and accumulating evidence indicates that it functions as an oncogene. Since miRNAs suppress the expression of their target genes, we hypothesized that some miR-21 targets may act as tumor suppressors, and thus their expression would be anticipated to be reduced by the high miR-21 levels observed in various human cancers. By microarray analysis and quantitative PCR we identified and validated FBXO11 (a member of the F-box subfamily lacking a distinct unifying domain) as a miR-21 target gene. FBXO11 is a component of the SKP1-CUL1-F-box ubiquitin ligase complex that targets proteins for ubiquitination and proteosomal degradation. By loss of function and gain of function studies, we show that FBXO11 acts as a tumor suppressor, promotes apoptosis and mediates the degradation of the oncogenic protein BCL6. The critical role that FBXO11 plays in miR-21-mediated tumorigenesis was demonstrated by a rescue experiment, in which silencing FBXO11 in miR-21KD cancer cells restored their high tumorigenicity. Expression of miR-21 and FBXO11 are inversely correlated in tumor tissue, and their expression correlates with patient survival and tumor grade. High FBXO11 expression correlates with better patient survival and lower tumor grade consistent with its tumor suppressor activity. In contrast high miR-21 expression, which correlates with poor patient survival and higher tumor grade, is consistent with its oncogenic activity. Our results identify FBXO11 as a novel miR-21 target gene, and demonstrate that the oncogenic miRNA miR-21 decreases the expression of FBXO11, which normally acts as a tumor suppressor, and thereby promotes tumorigenesis.
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Pfeffer
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sims
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Linga
authors.affiliation: Surgery, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Paulus
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: From the Departments of Pathology and Laboratory Medicine, the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and lpfeffer@uthsc.edu.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: FBXO11; cancer; glioblastoma; melanoma; miR-21; microRNA (miRNA); prostate cancer; tumor suppressor gene