Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma.
Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma.
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DOI：
10.18632/oncotarget.622
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
Asangani IA;Harms PW;Dodson L;Pandhi M;Kunju LP;Maher CA;Fullen DR;Johnson TM;Giordano TJ;Palanisamy N;Chinnaiyan AM
microRNAs（miRs）通过协同抑制参与细胞增殖、迁移和侵袭的众多靶基因在癌症病因学中起关键作用。染色体9 p21中包含miR-31的基因组区域在包括黑素瘤在内的实体癌中经常缺失;然而，miR-31的表达和功能作用先前尚未在黑素瘤中研究。在这里，我们查询的表达状态，并进行功能表征的miR-31在黑色素瘤组织和细胞系。我们发现miR-31的下调是黑色素瘤肿瘤和细胞系中的常见事件，并且与样本子集中的基因组丢失相关。miR-31基因表达的下调也是通过DNA甲基化和EZH 2介导的组蛋白甲基化引起的表观遗传沉默的结果。miR-31在各种黑色素瘤细胞系中的异位过表达抑制细胞迁移和侵袭。miR-31靶标包括致癌激酶如SRC、MET、NIK（MAP 3 K14）和黑素瘤特异性致癌基因RAB 27 a。此外，miR-31过表达导致EZH 2下调及其靶基因rap 1GAP的去抑制; EZH 2表达增加与黑色素瘤进展和患者总体生存相关。总之，我们的研究支持miR-31在黑色素瘤中的肿瘤抑制作用，并确定了新的治疗靶点。
MicroRNAs (miRs) play a key role in cancer etiology by coordinately repressing numerous target genes involved in cell proliferation, migration and invasion. The genomic region in chromosome 9p21 that encompasses miR-31 is frequently deleted in solid cancers including melanoma; however the expression and functional role of miR-31 has not been previously studied in melanoma. Here, we queried the expression status and performed functional characterization of miR-31 in melanoma tissues and cell lines. We found that down-regulation of miR-31 was a common event in melanoma tumors and cell lines and was associated with genomic loss in a subset of samples. Down-regulation of miR-31 gene expression was also a result of epigenetic silencing by DNA methylation, and via EZH2-mediated histone methylation. Ectopic overexpression of miR-31 in various melanoma cell lines inhibited cell migration and invasion. miR-31 targets include oncogenic kinases such as SRC, MET, NIK (MAP3K14) and the melanoma specific oncogene RAB27a. Furthermore, miR-31 overexpression resulted in down-regulation of EZH2 and a de-repression of its target gene rap1GAP; increased expression of EZH2 was associated with melanoma progression and overall patient survival. Taken together, our study supports a tumor suppressor role for miR-31 in melanoma and identifies novel therapeutic targets.
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影响因子：
37.3
作者：
Augoff K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
DOI：
10.1111/j.1440-1746.2008.05666.x
发表时间：
2009-04-01
影响因子：
4.1
作者：
Guo, Junming;Miao, Ying;Wang, Yanjun
通讯作者：
Wang, Yanjun
影响因子：
4.8
作者：
Dhawan, P;Richmond, A
通讯作者：
Richmond, A
影响因子：
37.3
作者：
Bandrés E;Cubedo E;Agirre X;Malumbres R;Zárate R;Ramirez N;Abajo A;Navarro A;Moreno I;Monzó M;García-Foncillas J
通讯作者：
García-Foncillas J
影响因子：
15.9
作者：
Liu, Xi;Sempere, Lorenzo F.;Dmitrovsky, Ethan
通讯作者：
Dmitrovsky, Ethan