Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Am J Pathol. 2019 Oct;189(10):1973-1985. doi: 10.1016/j.ajpath.2019.06.006. Epub 2019 Jul 16.
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 G/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.
容积调节阴离子通道由富含亮氨酸重复序列的蛋白 A（LRRC8A）组成，受低渗条件激活，实现调节性细胞体积减少的过程。本研究探讨了 LRRC8A 在调节食管鳞癌（ESCC）进展相关基因中的作用，以及 LRRC8A 表达在这种肿瘤中的预后意义。使用 ESCC 细胞系和 LRRC8A siRNA 进行敲低实验，评估该蛋白对肿瘤功能的影响。此外，通过微阵列分析确定 ESCC 的基因表达谱。对接受根治性食管切除术的 64 例 ESCC 患者的 64 个原发肿瘤样本进行免疫组织化学染色。结果发现，LRRC8A 耗竭可降低细胞增殖和迁移，促进细胞凋亡。微阵列数据分析显示，LRRC8A 耗竭细胞中存在 G1/S 检查点调控以及磷脂酰肌醇 3-激酶/AKT 信号、基质金属蛋白酶和整合素信号相关基因（包括 p21、p27、MMP1 和 ITGAV）的上调或下调。免疫组织化学染色显示，LRRC8A 表达与病理 N 和 T 分期类别有关，LRRC8A 强表达与 ESCC 的预后不良相关。这些发现表明，LRRC8A 通过影响细胞周期、凋亡和迁移来调节肿瘤进展，为其作为 ESCC 效应因子或生物标志物的功能提供了新的见解。
