The expression of the alpha1 subunit of Na+/K+-ATPase is related to tumor development and clinical outcomes in gastric cancer
The expression of the alpha1 subunit of Na+/K+-ATPase is related to tumor development and clinical outcomes in gastric cancer
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Na+/K+- atp酶α 1亚基的表达与胃癌的发展和临床结局有关
DOI：
10.1007/s10120-021-01212-6
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发表时间：
2021-07-12
期刊：
影响因子：
7.4
通讯作者：
Otsuji, Eigo
中科院分区：
文献类型：
--
作者：
Nakamura, Kei;Shiozaki, Atsushi;Otsuji, Eigo
背景Na+/K+-ATP酶α 1亚基（ATP 1A 1）是Na+/K+-ATP酶（NKA）的重要组成部分，NKA是维持细胞内低Na+/K+比值、维持细胞体积和渗透压的膜泵。ATP 1A 1与肿瘤行为有关。因此，本研究探讨ATP 1A 1在胃癌（GC）患者中的作用。方法应用ATP 1A 1 siRNA对人胃癌细胞株进行敲低实验，观察ATP 1A 1 siRNA对胃癌细胞增殖、细胞周期、凋亡及细胞运动的影响。通过微阵列分析进行基因表达谱分析。对192例接受胃切除术的胃癌患者的原发性肿瘤样本进行免疫组化分析。结果ATP 1A 1在NUGC 4和MKN 74细胞中高表达。细胞增殖受到抑制，并诱导凋亡的siRNA诱导敲低ATP 1A 1。微阵列分析显示，ATP 1A 1的敲低导致干扰素（IFN）信号通路相关基因的表达上调，如STAT 1、STAT 2、IRF 1和IRF 9。此外，ATP 1A 1的耗竭改变了MAPK通路的磷酸化。免疫组化分析显示，ATP 1A 1的表达与组织学类型、静脉浸润和病理T分期有关。此外，预后分析显示ATP 1A 1高表达水平与术后生存率差相关。结论ATP 1A 1可能通过改变IFN信号通路调控胃癌的进展，ATP 1A 1高表达与胃癌患者术后生存率相关。目前的研究结果提供了新的见解ATP 1A 1的功能作为一个调解人和/或生物标志物的GC。
Background The Na+/K+-ATPase alpha1 subunit (ATP1A1) is a critical component of Na+/K+-ATPase (NKA), a membrane pump that maintains a low intracellular Na+/K+ ratio and retains cellular volume and osmolarity. ATP1A1 was recently implicated in tumor behavior. Therefore, the present study investigated the role of ATP1A1 in patients with gastric cancer (GC). Methods Knockdown experiments were conducted on human GC cell lines using ATP1A1 siRNA, and its effects on proliferation, the cell cycle, apoptosis, and cellular movement were examined. Gene expression profiling was performed by a microarray analysis. Primary tumor samples from 192 GC patients who underwent gastrectomy were subjected to an immunohistochemical analysis. Results High ATP1A1 expression levels were observed in NUGC4 and MKN74 cells. Cell proliferation was suppressed and apoptosis was induced by the siRNA-induced knockdown of ATP1A1. The microarray analysis showed that knockdown of ATP1A1 leads to the up-regulated expression of genes involved in the interferon (IFN) signaling pathway, such as STAT1, STAT2, IRF1, and IRF9. Furthermore, the depletion of ATP1A1 altered the phosphorylation of the MAPK pathway. The immunohistochemical analysis revealed that the expression of ATP1A1 was associated with the histological type, venous invasion, and the pathological T stage. Furthermore, the prognostic analysis showed a relationship between high ATP1A1 expression levels and poor postoperative survival. Conclusions ATP1A1 appears to regulate tumor progression by altering IFN signaling, and high ATP1A1 expression levels were associated with poor postoperative survival in GC patients. The present results provide novel insights into the function of ATP1A1 as a mediator and/or biomarker of GC.