Abstract
MicroRNAs (miRNAs) play a critical role in gastric cancer progression and metastasis. This study investigated the role of miRNA-135a in early gastric cancer (EGC) including lymph node (LN) metastasis. We examined the correlation between miRNA-135a expression and clinical outcomes in 59 patients who underwent surgery for EGC. Using gastric cancer cell lines, we performed functional and target gene analyses. miRNA-135a expression was down-regulated in 33.9% of patients. These patients showed a significantly more advanced stage (TNM stage≥IB, 35.0% vs. 12.8%, p = 0.045) and higher rate of LN metastasis (30.0% vs. 5.1%, p = 0.014) than those with up-regulation of miRNA-135a expression. In a multivariate analysis, down-regulation of miRNA-135a was an independent risk factor for LN metastasis (adjusted odds ratio, 8.04; 95% confidence interval, 1.08–59.81; p = 0.042). Functional analyses using gastric cancer cell lines showed that miRNA-135a suppressed cell viability, epithelial-mesenchymal transition, cell invasion, and migration. ROCK1 was a target of miRNA-135a and its expression was inversely correlated to that of miRNA-135a. ROCK1 expression was significantly increased in EGC patients with LN metastasis than in those without LN metastasis. Our results confirm the tumor-suppressive role of miRNA-135a, and demonstrate its role in LN metastasis in EGC. miRNA-135a and its target gene ROCK1 may be novel therapeutic and prognostic targets for EGC.
Highlights
Gastric cancer still remains the second most common cause of cancer mortality worldwide, despite decreasing incidence and mortality rates in developed countries [1].In areas, including Korea and Japan, where screening for gastric cancer is performed widely, early detection is often possible
A multivariate logistic regression analysis showed that miRNA-135a down-regulation was independently associated with lymph node (LN) metastasis
We identified a new target gene of miRNA-135a, ROCK1, which was associated with LN metastasis in gastric cancer
Summary
Gastric cancer still remains the second most common cause of cancer mortality worldwide, despite decreasing incidence and mortality rates in developed countries [1].In areas, including Korea and Japan, where screening for gastric cancer is performed widely, early detection is often possible. Because an increased rate of early detection of gastric cancer can lead to an improved prognosis, interests in improving patients’ quality of life and utilizing minimally invasive treatments have increased. In patients with gastric cancer, lymph node (LN) metastasis is one of the most important prognostic factors, and the overall incidence of a LN metastasis in early gastric cancer (EGC) ranges from 5 to 20% [2,3,4]. Gastrectomy with LN dissection is regarded as the standard treatment for gastric cancer; 80 to 95% of patients with EGC do not require a LN dissection if the gastric cancer is completely excised by less invasive treatments such as endoscopic resection [5,6,7] or minimally invasive surgery (e.g., simple wedge resection or sentinel LN navigation surgery) [8,9,10]. Studies of biologic prognostic and predictive markers for LN metastasis in EGC have been conducted, no predictive tools exist for nodal metastasis of EGC
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