RUNX3 inhibits the invasion and migration of esophageal squamous cell carcinoma by reversing the epithelial-mesenchymal transition through TGF-β/Smad signaling

Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor, and its inactivation may play a crucial role in the carcinogenesis process of numerous cancer types, including esophageal squamous cell carcinoma (ESCC). We previously revealed that RUNX3 inactivation was correlated with lymph node metastasis (LNM) and ESCC recurrence. However, the exact mechanisms of this process are still under investigation. The aim of the present study was to examine the potential roles and underlying molecular mechanisms of RUNX3 in ESCC metastasis and the epithelial-mesenchymal transition (EMT). According to the results, RUNX3 expression in ESCC tissue was significantly reduced compared with that in adjacent normal tissue (0.50±0.20 vs. 0.83±0.16; P<0.001). In addition, statistical analysis revealed a close association between decreased RUNX3 expression and T status (P=0.027) and LNM (P=0.017) in ESCC patients. Pearson's correlation coefficient analysis was then used to evaluate correlations between RUNX3 and EMT-related marker expression. The results revealed that RUNX3 expression in ESCC tissues was negatively correlated with the expression of N-cadherin (r=−0.429; P<0.01) and Snail (r=−0.364; P<0.01) and positively correlated with the expression of E-cadherin (r=0.580; P<0.01). Moreover, Eca109 and EC9706 cell invasion, migration, MMP-9 expression and EMT were significantly inhibited by RUNX3 overexpression. Notably, further analysis revealed that RUNX3 overexpression markedly inhibited the phosphorylation of Smad2/3; RUNX3-overexpressing cells also displayed less sensitivity to TGF-β1-induced EMT than control cells. Thus, RUNX3 may inhibit the invasion and migration of ESCC cells by reversing EMT through TGF-β/Smad signaling and may be useful as a therapeutic target.