MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway

Abstract

Increasing evidence has demonstrated that microRNAs (miRNAs or miRs) play a variety of roles in tumor development, progression and chemosensitivity in a wide range of tumors. In this study, we found that miR-125a-5p exhibited a low expression in esophageal squamous cell carcinoma (ESCC) tissues and cells, and that its low expression was associated with higher tumor staging and shorter a survival time of patients with ESCC. Moreover, miR-125a-5p overexpression contributed to the suppression of cell proliferation, cell cycle arrest, cell apoptosis and a decrease in cell migratory and invasive abilities, whereas the downregulation of miR-125a-5p promoted cell proliferation, accelerated cell cycle progression, suppressed apoptosis and enhanced the migratory and invasive abilities of ESCC EC1 and TE1 cells, which may be tightly associated with the epithelial-mesenchymal transition (EMT) process in ESCC. Importantly, miR-125a-5p enhanced the cytotoxic effects of cisplatin on EC1 and TE1 cells, and co-treatment with miR-125a-5p and cisplatin significantly induced cell apoptosis and reduced the cell migratory and invasive abilities of EC1 and TE1 cells, coupled with an increase in the E-cadherin level and a decrease in the N-cadherin and Vimentin levels. Most notably, signal transducer and activator of transcription-3 (STAT3) was found to be a direct target of miR-125a-5p in ESCC cells, and miR-125a-5p overexpression significantly reduced the protein levels of t-STAT3, p-STAT3 and vascular endothelial growth factor (VEGF) in EC1 and TE1 cells. Furthermore, the combination of miR-125a-5p and cisplatin markedly inactivated the STAT3 signaling pathway; however, interleukin (IL)-6, a widely reported activator of the STAT3 signaling pathway, reversed the suppressive effects of miR-125a-5p/cisplatin in ESCC cells on the activation of the STAT3 signaling pathway. Of note, we found that IL-6 markedly reversed the altered cell phenotype mediated by the combination of miR-125a-5p and cisplatin in ESCC cells. These findings suggest that miR-125a-5p may play a pivotal role in the development and progression of ESCC, which may be achieved via the manipulation of the STAT3 signaling pathway.