Genomic Loss of miR-486 Regulates Tumor Progression and the OLFM4 Antiapoptotic Factor in Gastric Cancer
Genomic Loss of miR-486 Regulates Tumor Progression and the OLFM4 Antiapoptotic Factor in Gastric Cancer
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DOI：
10.1158/1078-0432.ccr-10-3152
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发表时间：
2011-05-01
影响因子：
11.5
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Oh, Hue-Kian;Tan, Angie Lay-Keng;Tan, Patrick
目的：microRNAs(MiRNA)在多种人类癌症中发挥重要的致癌和抑癌作用。实验设计：利用Agilent miRNA芯片，比较40例原发胃肿瘤和40例胃正常组织的miRNA表达谱，鉴定在胃肿瘤中显著下调的miRNAs。结果：在胃肿瘤和正常胃组织中差异表达的前80个miRNAs中(假发现率为0.01)，我们鉴定出hsa-miR-486(miR-486)是在原发胃癌和GC细胞系中显著下调的miRNA。在胃癌细胞系(YCC3、SCH和AGS)中，miR-486的表达恢复可抑制一些癌前性状，而在YCC6 GC细胞中抑制miR-486的表达则促进细胞增殖。对106例原发癌的阵列-CGH分析显示，大约25%至30%的癌组织中存在miR-486基因座的基因组缺失，其中包括两个肿瘤局部基因组缺失，特别是miR-486基因缺失，这与miR-486发挥肿瘤抑制作用一致。生物信息学分析证实，分泌的抗凋亡糖蛋白OLFM4是miR-486的潜在靶点。在GC细胞中恢复miR-486的表达降低了内源性OLFM4的转录和蛋白水平，也抑制了含有预测miR-486结合位点的OLFM4 30非翻译区的荧光素酶报告的表达。OLFM4沉默也显著降低了胃癌细胞的增殖，支持了OLFM4作为miR-486靶点的生物学意义。结论：miR-486可能是一种新的胃癌抑制基因miRNA。其抗肿瘤活性可能与直接靶向和抑制OLFM4有关。临床癌症资源；17(9)；2657-67。(C)2011年AACR。
Purpose: MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC).Experimental Design: Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors.Results: Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target. Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 30 untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing.Conclusions: miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4. Clin Cancer Res; 17(9); 2657-67. (C)2011 AACR.