title: miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer.
abstract: Growing evidence suggests that microRNAs (miRNAs) are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the mechanism of carcinogenesis. However, the genetic or epigenetic regulations of these miRNAs have not yet been fully elucidated in bladder cancer (BC). Chromosomal alterations of cancer cells give us important information for the identification of tumor suppressor genes. Our miRNA array-comparative genomic hybridization (CGH) analysis showed several miRNAs to be candidate tumor suppressors of BC. Our array-CGH analysis revealed that chromosome 4 was lost in all BC cell lines. We selected 19 miRNAs located on chromosome 4 and evaluated their expression levels in cancer cell lines as well as clinical samples. Gain-of-function analysis revealed that miR-218 inhibited BC cell proliferation, migration and invasion. Furthermore, flow cytometry analysis showed that it induced BC cell apoptosis. Genome-wide gene expression analysis showed that it targeted multiple oncogenes in BC. Our study is the first to demonstrate that miR-218 located on chrosomosme 4p15.31 is a tumor suppressive miRNA in BC. The identification of tumor suppressive miRNAs and their target genes on the basis of array-CGH analysis could provide new insights into the mechanisms of BC carcinogenesis.
authors.affiliation: Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tatarano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Kazumori
authors.initials: K
authors.lastname: Kawakami
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Hideo
authors.initials: H
authors.lastname: Hidaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kawahara
authors.forename: Kenryu
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins