P2.29 miR-148a has a Therapeutic Potential to Suppress Gastric Cancer Metastasis

Abstract

ABSTRACT Gastric cancer (GC) is the second leading cause of cancer-related death worldwide, with an estimated one million new cases per year. Approximately 50 % of cases occur in Eastern Asia (mainly in China). In most patients, GC is diagnosed at advanced stage frequently accompanied by extensive invasion and lymphatic metastasis, successful therapeutic strategies are limited and the mortality is high. Therefore, investigations into the molecular mechanisms involving in GC progression have major importance and may tend to develop novel avenues for targeted therapy. MicroRNAs (miRNAs) 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 (GC) metastasis. We found that miR-148a expression was suppressed by more than 4 folds in GC compared with their corresponding non-tumorous tissues (90 paired), and the downregulated miR-148a was significantly associated with TNM stage and lymph-node metastasis. Functional assays demonstrated that overexpression of miR-148a suppressed GC cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, we found that miR-148a could target RhoA/ROCK signaling pathway through downregulating ROCK1. 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 two sites of 3' untranslated region of ROCK1. Moreover, in GC tissues, we observed an inverse correlation between miR-148a and ROCK1 expression. Knockdown of ROCK1 significantly inhibited GC cell migration and invasion resembling that of miR-148a overexpression. We further found that ROCK1 was involved in miR-148a-induced suppression of GC cell migration and invasion. Taken together, our results show that miR-148a functions as a tumor metastasis suppressor in GC, and downregulation of miR-148a contributes to GC lymph-node metastasis and progression. By understanding the function and molecular mechanism of miR-148a in GC, miR-148a may have a therapeutic potential to suppress GC metastasis. (Clin Cancer Res; 17(24); 7574-83) Download : Download full-size image Fig. 1 . miR-148a is downregulated in GC and associated with advanced clinical stage and lymph-node metastasis.