Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.
Cancer Sci. 2014 Feb;105(2):236-43. doi: 10.1111/cas.12330. Epub 2014 Jan 6.
Gastric cancer (GC) develops through deregulation of gene expression and accumulation of epigenetic abnormalities, leading to tumor cell acquisition of malignant features. MicroRNAs (miRNAs) play a critical role in cancer development where they can act as oncogenes or oncosuppressors. To identify miRNAs that are associated with some clinicopathologic features of GC and/or participate in tumor progression, miRNA expression in 20 GC tissues and five corresponding non-neoplastic gastric mucosa was examined by miRNA microarray. Oligonucleotide array analysis was carried out for miRNA target prediction. The functions of candidate miRNAs and their target genes were also analyzed by quantitative RT-PCR, Western blotting, reporter gene assay, and cell invasion assay. Comparison of miRNA expression profiles revealed that downregulation of miR-148a was identified in most of the GC tissues. Downregulation of miR-148a was significantly correlated with an advanced clinical stage, lymph node metastasis, and poor clinical outcome. Custom oligonucleotide array analysis revealed that MMP7 expression was markedly downregulated in miR-148a-overexpressing GC cells; MMP7 was found to be a direct and functional target of miR-148a, participating in cell invasion. These results suggest that miR-148a contributes to the maintenance of homeostasis in normal stomach tissue and plays an important role in GC invasion by regulating MMP7 expression.
胃癌（GC）的发生是由于基因表达失调和表观遗传异常的积累，导致肿瘤细胞获得恶性特征。microRNAs（miRNAs）在癌症的发生发展中起着至关重要的作用，它们可以作为癌基因或抑癌基因发挥作用。为了鉴定与 GC 的某些临床病理特征相关或参与肿瘤进展的 miRNAs，通过 miRNA 微阵列检测了 20 个 GC 组织和 5 个相应的非肿瘤性胃黏膜中的 miRNA 表达。进行了寡核苷酸阵列分析以预测 miRNA 靶标。还通过定量 RT-PCR、Western blotting、报告基因测定和细胞侵袭测定分析候选 miRNA 及其靶基因的功能。miRNA 表达谱的比较表明，miR-148a 在大多数 GC 组织中下调。miR-148a 的下调与临床分期较晚、淋巴结转移和不良临床结局显著相关。定制的寡核苷酸阵列分析显示，MMP7 表达在 miR-148a 过表达的 GC 细胞中显著下调；MMP7 被发现是 miR-148a 的直接和功能靶标，参与细胞侵袭。这些结果表明，miR-148a 通过调节 MMP7 的表达，有助于维持正常胃组织的内稳态，并在 GC 侵袭中发挥重要作用。
