Abstract
The volume-regulated anion channel is composed of leucine-rich repeat-containing protein A (LRRC8A) and is activated by hypotonic conditions to implement the process of regulatory volume decrease. The role of LRRC8A in regulating genes related to progression of esophageal squamous cell carcinoma (ESCC) was investigated, as well as the prognostic significance of LRRC8A expression in this tumor. Knockdown experiments were conducted using ESCC cell lines and LRRC8A siRNA to assess the influence of this protein on tumor function. In addition, the gene expression profile of ESCC was determined by microarray analysis. Immunohistochemistry was performed on 64 primary tumor samples from ESCC patients receiving radical esophagectomy. It was found that depletion of LRRC8A decreased cell proliferation and migration and also promoted apoptosis. Microarray data demonstrated G1/S checkpoint regulation and up-regulation or down-regulation of phosphatidylinositol 3-kinase/AKT signaling, matrix metalloproteinase, and integrin signaling-related genes (including p21, p27, MMP1, and ITGAV) in LRRC8A-depleted cells. Immunohistochemistry showed that LRRC8A expression was related to the pathologic N and T stage categories, and strong LRRC8A expression was correlated with a worse prognosis of ESCC. These findings indicate that LRRC8A modulates tumor progression by influencing cell cycle, apoptosis, and migration, providing new insights into its function as an effector or biomarker of ESCC.