title: Overexpression of miR-210, a downstream target of HIF1α, causes centrosome amplification in renal carcinoma cells.
abstract: MiR-210 is significantly up-regulated in clear cell renal cell carcinoma (CCC), but the mechanism and biological consequences of miR-210 up-regulation are poorly understood. Here, we show that miR-210 is highly expressed in renal carcinoma cell lines and that its expression is clearly correlated with accumulation of hypoxia-inducible factor 1α (HIF1α) under normoxia as well as hypoxia, suggesting that miR-210 up-regulation in renal carcinoma cells is most likely due to accumulation of HIF1α. To reveal the effects of miR-210 up-regulation, the miR-210 precursor was transfected into renal carcinoma cells. After transfection, the cells accumulated at the G2/M phase of the cell cycle and their viability was decreased, suggesting that miR-210 overexpression may trigger an event that hinders normal cell division. Immunocytochemistry demonstrated a multipolar spindle accompanied by centrosome amplification in cells overexpressing miR-210. It has been reported that centrosome amplification induces chromosome mis-segregation, finally leading to chromosome instability and aneuploidy. Indeed, the proportion of aneuploid cells (>4n) was increased in miR-210 overexpressed cells. By using the TargetScan and PicTar algorithms, E2F3 was identified as one of the possible targets of miR-210 and was suppressed at the protein level by miR-210. Moreover, the proportion of aneuploid cells was increased in E2F3 siRNA transfected cells. On the basis of these results, we propose that miR-210 up-regulation due to HIF1α accumulation may induce aneuploidy via E2F3 down-regulation at least in part, and may play a role in tumourigenesis and/or progression of CCC.
authors.affiliation: Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsuura
authors.forename: Tung Lam
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Naoki
authors.initials: N
authors.lastname: Hijiya
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Moriyama
mesh_terms: D000782:Aneuploidy; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D002453:Cell Cycle / Q000235:genetics; D018385:Centrosome / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D035683:MicroRNAs / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins