title: Human glioma growth is controlled by microRNA-10b.
abstract: MicroRNA (miRNA) expression profiling studies revealed a number of miRNAs dysregulated in the malignant brain tumor glioblastoma. Molecular functions of these miRNAs in gliomagenesis are mainly unknown. We show that inhibition of miR-10b, a miRNA not expressed in human brain and strongly upregulated in both low-grade and high-grade gliomas, reduces glioma cell growth by cell-cycle arrest and apoptosis. These cellular responses are mediated by augmented expression of the direct targets of miR-10b, including BCL2L11/Bim, TFAP2C/AP-2γ, CDKN1A/p21, and CDKN2A/p16, which normally protect cells from uncontrolled growth. Analysis of The Cancer Genome Atlas expression data set reveals a strong positive correlation between numerous genes sustaining cellular growth and miR-10b levels in human glioblastomas, while proapoptotic genes anticorrelate with the expression of miR-10b. Furthermore, survival of glioblastoma patients expressing high levels of miR-10 family members is significantly reduced in comparison to patients with low miR-10 levels, indicating that miR-10 may contribute to glioma growth in vivo. Finally, inhibition of miR-10b in a mouse model of human glioma results in significant reduction of tumor growth. Altogether, our experiments validate an important role of miR-10b in gliomagenesis, reveal a novel mechanism of miR-10b-mediated regulation, and suggest the possibility of its future use as a therapeutic target in gliomas.
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Gabriely
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Narayan
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Niers
authors.forename: Thomas
authors.initials: T
authors.lastname: Wurdinger
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Christine
authors.initials: C
authors.lastname: Esau
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis*
chemical_list: C547183:MIRN10 microRNA, human; D035683:MicroRNAs