Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Clin Cancer Res. 2011 Dec 15;17(24):7574-83. doi: 10.1158/1078-0432.CCR-11-1714. Epub 2011 Oct 12.
MicroRNAs (miRNA) have been documented playing a critical role in cancer development and progression. In this study, we investigate the role of miR-148a in gastric cancer metastasis.
We examined miR-148a levels in 90 gastric cancer samples by qRT-PCR and analyzed the clinicopathologic significance of miR-148a expression. The gastric cancer cells stably expressing miRNA-148a were analyzed for migration and invasion assays in vitro and metastasis assays in vivo; the target genes of miR-148a were further explored.
We found that miR-148a expression was suppressed by more than 4-fold in gastric cancer compared with their corresponding nontumorous tissues, and the downregulated miR-148a was significantly associated with tumor-node-metastasis (TNM) stage and lymph node-metastasis. Functional assays showed that overexpression of miR-148a suppressed gastric cancer cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, overexpression of miR-148a in GC cells could reduce the mRNA and protein levels of ROCK1, whereas miR-148a silencing significantly increased ROCK1 expression. Luciferase assays confirmed that miR-148a could directly bind to the 2 sites of 3' untranslated region of ROCK1. Moreover, in gastric cancer tissues, we observed an inverse correlation between miR-148a and ROCK1 expression. Knockdown of ROCK1 significantly inhibited gastric cancer cell migration and invasion resembling that of miR-148a overexpression. We further found that ROCK1 was involved in miR-148a-induced suppression of gastric cancer cell migration and invasion.
miR-148a functions as a tumor metastasis suppressor in gastric cancer, and downregulation of miR-148a contributes to gastric cancer lymph node-metastasis and progression. miR-148a may have a therapeutic potential to suppress gastric cancer metastasis.
MicroRNAs（miRNA）已被证明在癌症的发生和发展中起着关键作用。在这项研究中，我们研究了 miR-148a 在胃癌转移中的作用。
我们通过 qRT-PCR 检测了 90 例胃癌样本中的 miR-148a 水平，并分析了 miR-148a 表达的临床病理意义。通过体外迁移和侵袭实验以及体内转移实验分析稳定表达 miRNA-148a 的胃癌细胞；进一步探索了 miR-148a 的靶基因。
与相应的非肿瘤组织相比，胃癌中 miR-148a 的表达被抑制了 4 倍以上，下调的 miR-148a 与肿瘤-淋巴结-转移（TNM）分期和淋巴结转移显著相关。功能分析表明，过表达 miR-148a 可抑制胃癌细胞的体外迁移和侵袭以及体内肺转移的形成。此外，GC 细胞中 miR-148a 的过表达可降低 ROCK1 的 mRNA 和蛋白水平，而 miR-148a 沉默可显著增加 ROCK1 的表达。荧光素酶实验证实 miR-148a 可直接结合 ROCK1 3'非翻译区的 2 个位点。此外，在胃癌组织中，我们观察到 miR-148a 与 ROCK1 表达呈负相关。ROCK1 的敲低显著抑制了类似于 miR-148a 过表达的胃癌细胞的迁移和侵袭。我们进一步发现，ROCK1 参与了 miR-148a 诱导的胃癌细胞迁移和侵袭抑制。
miR-148a 在胃癌中作为肿瘤转移抑制因子发挥作用，下调 miR-148a 有助于胃癌淋巴结转移和进展。miR-148a 可能具有抑制胃癌转移的治疗潜力。
