Bae Jin-Han, Kang Myoung Joo, Yang Kwang-Mo, Kim Tae-Oh, Yi Joo Mi
Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan 619-953, Republic of Korea.
Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan 612-896, Republic of Korea.
Oncol Rep. 2015 Aug;34(2):1017-26. doi: 10.3892/or.2015.4036. Epub 2015 Jun 5.
microRNAs (miRNAs), which are small non‑coding RNA molecules, can participate in diverse biological functions and act as oncogenes or tumor suppressors by inhibiting target gene expression. The alteration of miRNA expression is observed in many types of human cancers and has been implicated in carcinogenesis. Since miRNAs have been known to be downregulated in most cancer types, there is growing evidence that several miRNAs are downregulated by DNA hypermethylation. Here, we determined that MIR219.2, MIR663b and MIR1237 were transcriptionally silenced by DNA hypermethylation in human gastric cancer cell lines. Moreover, we demonstrated the functional roles of these epigenetically silenced miRNAs by ectopically expressing them in gastric cancer cells, which caused the suppression of growth and proliferation. In addition, wound closure, cell migration, and invasion were significantly reduced in AGS cells following transfection with MIR219.2, MIR663b or MIR1237 mimics. Notably, epithelial-to-mesenchymal transition (EMT)-associated proteins were decreased in response to ectopic expression of these miRNAs, supporting the notion that these miRNAs have a tumor-suppressive effect in gastric cancer. We finally predicted the targets of these miRNAs and identified several candidate genes, the expression levels of which were significantly downregulated by ectopic expression of MIR219.2, MIR663b or MIR1237 mimics in the gastric cancer cell lines. Our study provides strong evidence that these miRNAs are transcriptionally regulated by DNA methylation in gastric cancer and have tumor-suppressive roles by decreasing the mesenchymal traits in cancer as well as by targeting cancer-associated genes.
微小RNA（miRNA）是一类小的非编码RNA分子，可参与多种生物学功能，并通过抑制靶基因表达发挥癌基因或肿瘤抑制因子的作用。在多种人类癌症中均观察到miRNA表达的改变，其与癌症发生有关。由于已知大多数癌症类型中miRNA表达下调，越来越多的证据表明一些miRNA因DNA高甲基化而下调。在此，我们确定在人胃癌细胞系中，MIR219.2、MIR663b和MIR1237因DNA高甲基化而发生转录沉默。此外，我们通过在胃癌细胞中异位表达这些表观遗传沉默的miRNA，证明了它们的功能作用，这导致细胞生长和增殖受到抑制。另外，用MIR219.2、MIR663b或MIR1237模拟物转染AGS细胞后，伤口闭合、细胞迁移和侵袭均显著减少。值得注意的是，这些miRNA的异位表达导致上皮-间质转化（EMT）相关蛋白减少，支持了这些miRNA在胃癌中具有肿瘤抑制作用的观点。我们最终预测了这些miRNA的靶标，并鉴定了几个候选基因，在胃癌细胞系中，MIR219.2、MIR663b或MIR1237模拟物的异位表达显著下调了这些基因的表达水平。我们的研究提供了强有力的证据，表明这些miRNA在胃癌中受DNA甲基化转录调控，并通过降低癌症中的间质特征以及靶向癌症相关基因发挥肿瘤抑制作用。
