Wu I-Chen, Chen Yu-Kuei, Wu Chun-Chieh, Cheng Yu-Jen, Chen Wei-Chung, Ko Huey-Jiun, Liu Yu-Peng, Chai Chee-Yin, Lin Hung-Shun, Wu Deng-Chyang, Wu Ming-Tsang
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Oncotarget. 2016 Dec 20;7(51):85244-85258. doi: 10.18632/oncotarget.13267.
This study aims to identify new upregulated genes related to secretory or membranous proteins to help detect esophageal squamous cell carcinoma (ESCC). First, we performed microarray-based screening of esophageal tumors from both N-nitrosomethylbenzylamine- and arecoline-induced F344 rats and seventeen human ESCC specimens. Candidate genes were validated by quantitative PCR (qPCR) and immunohistochemical (IHC) staining of ESCC tissues. Among the paired cancer and adjacent normal tissues from 14 ESCC patients, 10 pairs (71.4%) had overexpression of ATP1A1 (ATPase Na+/K+ transporting alpha 1 polypeptide) by qPCR (P = 0.0052). ATP1A1 protein expression was re-confirmed by tissue arrays in 243 ESCC tissues and 126 adjacent normal tissues and by ELISA in 78 serum specimens of ESCC patients. ATP1A1 was 12.3 times (adjusted odds ratio=12.3, 95% CI = 7.2-21.0) more likely to be overexpressed in cancer tissues than in normal tissues. ATP1A1 expression was also correlated to tumor stage. Patients with higher serum ATP1A1 levels had a 2.9-fold (95% CI = 1.1-7.4) risk of late-stage disease (stages III-IV vs. I-II). Downregulation of ATP1A1 expression inhibited the migration and invasion ability of ESCC cell lines in vitro. We concluded that the overexpression of ATP1A1 is strongly associated with the presence and severity of ESCC.
本研究旨在鉴定与分泌性或膜蛋白相关的新上调基因，以帮助检测食管鳞状细胞癌（ESCC）。首先，我们对N-亚硝基甲基苄胺和槟榔碱诱导的F344大鼠的食管肿瘤以及17例人类ESCC标本进行了基于微阵列的筛选。候选基因通过ESCC组织的定量PCR（qPCR）和免疫组织化学（IHC）染色进行验证。在14例ESCC患者的配对癌组织和相邻正常组织中，10对（71.4%）通过qPCR检测到ATP1A1（ATP酶Na+/K+转运α1多肽）过表达（P = 0.0052）。通过组织芯片在243例ESCC组织和126例相邻正常组织中以及通过ELISA在78例ESCC患者血清标本中再次确认了ATP1A1蛋白表达。ATP1A1在癌组织中过表达的可能性是正常组织的12.3倍（调整优势比=12.3，95%CI = 7.2-21.0）。ATP1A1表达也与肿瘤分期相关。血清ATP1A1水平较高的患者发生晚期疾病（III-IV期与I-II期）的风险高2.9倍（95%CI = 1.1-7.4）。ATP1A1表达下调抑制了ESCC细胞系在体外的迁移和侵袭能力。我们得出结论，ATP1A1的过表达与ESCC的存在和严重程度密切相关。
