MicroRNA-125a-5p Is an Independent Prognostic Factor in Gastric Cancer and Inhibits the Proliferation of Human Gastric Cancer Cells in Combination with Trastuzumab

Purpose: MicroRNA 125a-5p (miR-125a-5p) has been reported to be a tumor suppressor in malignancies of the breast, ovary, lung, and central nervous system. However, the clinical significance of miR-125a-5p in human gastrointestinal cancer has not been explored. We investigated a tumor inhibitory effect of miR-125a-5p in gastric cancer, focusing in particular on the miR-125a-ERBB2 (HER2, HER-2/neu) pathway. Experimental Design: Quantitative RT-PCR was used to evaluate miR-125a-5p expression in 87 gastric cancer cases to determine the clinicopathologic significance of miR-125a-5p expression. The regulation of ERBB2 by miR-125a-5p was examined with precursor miR-125a-transfected cells. Furthermore, we investigated whether miR-125a-5p suppresses proliferation of gastric cancer cells in combination with trastuzumab, a monoclonal antibody against ERBB2. Results: Low expression levels of miR-125a-5p were associated with enhanced malignant potential such as tumor size (P = 0.0068), tumor invasion (P = 0.031), liver metastasis (P = 0.029), and poor prognosis (P = 0.0069). Multivariate analysis indicated that low miR-125a-5p expression was an independent prognostic factor for survival. In vitro assays showed that ERBB2 is a direct target of miR-125a-5p, which potently suppressed the proliferation of gastric cancer cells, and, interestingly, the growth inhibitory effect was enhanced in combination with trastuzumab. Conclusions: miR-125a-5p is a meaningful prognostic marker. Furthermore, miR-125a-5p mimic alone or in combination with trastuzumab could be a novel therapeutic approach against gastric cancer. Clin Cancer Res; 17(9); 2725-33. (C)2011 AACR.