Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ann Surg Oncol. 2023 Oct;30(11):6898-6910. doi: 10.1245/s10434-023-13779-8. Epub 2023 Jul 5.
Na/K-ATPase α1 subunit (ATP1A1) exhibits aberrant expression in various types of cancer. Moreover, its levels in specific tissues are associated with the development of cancer. Nevertheless, the mechanism and signaling pathways underlying the effects of ATP1A1 in colon cancer (CC) have not been elucidated, and its prognostic impact remains unknown.
Knockdown of ATP1A1 expression was performed in human CC cell lines HT29 and Caco2 using small interfering RNA. The roles of ATP1A1 in various biological processes of cells (i.e., proliferation, cell cycle, apoptosis, migration, and invasion) were assessed. Microarray analysis was utilized for gene expression profiling. Samples obtained from 200 patients with CC who underwent curative colectomy were analyzed through immunohistochemistry.
ATP1A1 knockdown suppressed cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that the upregulated or downregulated gene expression in ATP1A1-depleted cells was related to the extracellular signal-regulated kinase 5 (ERK5) signaling pathway [epidermal growth factor receptor (EGFR), mitogen-activated protein kinase kinase 5 (MAP2K5), mitogen-activated protein kinase 7 (MAPK7), FOS, MYC, and BCL2 associated agonist of cell death (BAD)]. Immunohistochemical analysis demonstrated a correlation between ATP1A1 expression and pathological T stage (p = 0.0054), and multivariate analysis identified high ATP1A1 expression as an independent predictor of poor recurrence-free survival in patients with CC (p = 0.0040, hazard ratio: 2.807, 95% confidence interval 1.376-6.196).
ATP1A1 regulates tumor progression through the ERK5 signaling pathway. High ATP1A1 expression is associated with poor long-term outcomes in patients with CC.
Na+/K+-ATPase α1 亚基（ATP1A1）在多种类型的癌症中表现出异常表达。此外，其在特定组织中的水平与癌症的发展有关。然而，ATP1A1 在结肠癌（CC）中的作用机制和信号通路尚未阐明，其预后影响尚不清楚。
使用小干扰 RNA 敲低人 CC 细胞系 HT29 和 Caco2 中的 ATP1A1 表达。评估 ATP1A1 在细胞各种生物学过程中的作用（即增殖、细胞周期、凋亡、迁移和侵袭）。利用微阵列分析进行基因表达谱分析。通过免疫组织化学分析了 200 例接受根治性结肠切除术的 CC 患者的样本。
ATP1A1 敲低抑制细胞增殖、迁移和侵袭，并诱导凋亡。微阵列分析的结果表明，ATP1A1 耗尽细胞中上调或下调的基因表达与细胞外信号调节激酶 5（ERK5）信号通路相关[表皮生长因子受体（EGFR）、丝裂原激活蛋白激酶激酶 5（MAP2K5）、丝裂原激活蛋白激酶 7（MAPK7）、FOS、MYC 和 BCL2 相关凋亡促进因子（BAD）]。免疫组织化学分析表明，ATP1A1 表达与病理 T 分期之间存在相关性（p=0.0054），多变量分析确定高 ATP1A1 表达是 CC 患者无复发生存不良的独立预测因子（p=0.0040，风险比：2.807，95%置信区间 1.376-6.196）。
ATP1A1 通过 ERK5 信号通路调节肿瘤进展。高 ATP1A1 表达与 CC 患者的长期预后不良相关。
