miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer
miR-218 on the genomic loss region of chromosome 4p15.31 functions as a tumor suppressor in bladder cancer
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DOI：
10.3892/ijo.2011.1012
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发表时间：
2011-07-01
影响因子：
5.2
通讯作者：
Nakagawa, Masayuki
中科院分区：
文献类型：
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作者：
Tatarano, Shuichi;Chiyomaru, Takeshi;Nakagawa, Masayuki
越来越多的证据表明，微小核糖核酸（miRNA）在多种人类癌症中存在异常表达，并且在癌症发生和发展过程中发挥着重要作用。鉴定具有肿瘤抑制作用的miRNA及其靶基因，有助于深入了解癌症发生的机制。然而，在膀胱癌（BC）中，这些miRNA的遗传或表观遗传调控机制尚未完全阐明。癌细胞的染色体改变为鉴定肿瘤抑制基因提供了重要信息。我们通过miRNA芯片 - 比较基因组杂交（CGH）分析，发现了几种可能作为膀胱癌肿瘤抑制因子的miRNA。我们的芯片 - CGH分析显示，所有膀胱癌细胞系中均存在4号染色体缺失。我们选取了位于4号染色体上的19种miRNA，并评估了它们在癌细胞系以及临床样本中的表达水平。功能获得性分析表明，miR - 218可抑制膀胱癌细胞的增殖、迁移和侵袭。此外，流式细胞术分析显示，它可诱导膀胱癌细胞凋亡。全基因组基因表达分析表明，它在膀胱癌中靶向多个癌基因。我们的研究首次证实，位于4p15.31染色体上的miR - 218是膀胱癌中的一种具有肿瘤抑制作用的miRNA。基于芯片 - CGH分析鉴定具有肿瘤抑制作用的miRNA及其靶基因，可为深入了解膀胱癌的发生机制提供新的思路。
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.