MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer

Biqiang Zheng, Linhui Liang, Chunmeng Wang, Shenglin Huang, Xi Cao, Ruopeng Zha, Li Liu, Deshui Jia, Qi Tian, Jianghong Wu, Yanwei Ye, Qifeng Wang, Ziwen Long, Ye Zhou, Chunyan Du, Xianghuo He, Yingqiang Shi
Clinical Cancer Research 2011 December 15, 17 (24): 7574-83

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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