Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, 501-1193, Japan.
Virchows Arch. 2021 Mar;478(3):401-411. doi: 10.1007/s00428-020-02899-1. Epub 2020 Aug 13.
This study was designed to unravel the pathobiological role of impaired ARID1A expression in gastric carcinogenesis. We examined ARID1A expression immunohistochemically in 98 gastric cancer tissue specimens with regard to the clinicopathological features. Based on the proportion and intensity of ARID1A immunoreactivity at the cancer invasion front, we subdivided the specimens into low- and high-expression ARID1A groups. Notably, low ARID1A expression was significantly correlated with overall survival of the patients. Subsequently, we determined the molecular signature that distinguished ARID1A low/poor prognosis from ARID1A high/good prognosis gastric cancers. A comprehensive gene profiling analysis followed by immunoblotting revealed that a mitochondrial apoptosis mediator, Harakiri, was less expressed in ARID1A low/poor prognosis than ARID1A high/good prognosis gastric cancers. siRNA-mediated ARID1A downregulation significantly reduced expression of the Harakiri molecule in cultured gastric cancer cells. Interestingly, downregulation of ARID1A conferred resistance to apoptosis induced by the mitochondrial metabolism inhibitor, devimistat. In contrast, enforced Harakiri expression restored sensitivity to devimistat-induced apoptosis in ARID1A downregulated gastric cancer cells. The present findings indicate that impaired ARID1A expression might lead to gastric carcinogenesis, putatively through gaining resistance to the Harakiri-mediated apoptosis pathway.
这项研究旨在揭示 ARID1A 表达受损在胃癌发生中的病理生物学作用。我们检测了 98 例胃癌组织标本中 ARID1A 的免疫组织化学表达情况，并分析了其与临床病理特征的关系。根据肿瘤侵袭前沿 ARID1A 免疫反应的比例和强度，我们将标本分为低表达和高表达 ARID1A 组。值得注意的是，低表达 ARID1A 与患者的总生存率显著相关。随后，我们确定了区分 ARID1A 低/预后不良和 ARID1A 高/预后良好的胃癌的分子特征。综合基因谱分析和免疫印迹显示，在 ARID1A 低/预后不良的胃癌中，线粒体凋亡介体 Harakiri 的表达低于 ARID1A 高/预后良好的胃癌。siRNA 介导的 ARID1A 下调显著降低了培养的胃癌细胞中 Harakiri 分子的表达。有趣的是，下调 ARID1A 可导致对线粒体代谢抑制剂 devimistat 诱导的细胞凋亡产生抗性。相比之下，在 ARID1A 下调的胃癌细胞中，强制表达 Harakiri 可恢复对 devimistat 诱导的细胞凋亡的敏感性。本研究结果表明，ARID1A 表达受损可能导致胃癌发生，这可能是通过获得对 Harakiri 介导的凋亡途径的抗性。
