Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.
Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.
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DOI：
10.18632/oncotarget.1903
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Pan Z
中科院分区：
文献类型：
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作者：
Zhu H;Zhang H;Jin F;Fang M;Huang M;Yang CS;Chen T;Fu L;Pan Z
恶性食管鳞状细胞癌（ESCC）迫切需要有效的治疗和预后生物标志物。本研究旨在鉴定涉及细胞内 Ca2+ 信号传导失调的致癌基因，已知该信号在细胞增殖和迁移中发挥重要作用。研究发现 ESCC 患者的肿瘤表现出 Orai1 表达升高，Orai1 是一种钙池操纵的 Ca2+ 进入 (SOCE) 通道，Orai1 的高表达与较差的总体生存率和无复发生存率相关。与非致瘤性上皮细胞的静止特性相反，人 ESCC 细胞的细胞内 Ca2+ 振荡表现出惊人的过度活跃，这对 Orai1 通道阻滞剂的治疗和 orai1 沉默敏感。此外，药物抑制Orai1活性或减少Orai1表达可抑制体外ESCC的增殖和迁移，并减缓体内异种移植小鼠中肿瘤的形成和生长。总而言之，这些发现提供了第一个证据，表明 Orai1 作为 ESCC 预后分层的新型生物标志物，并强调 Orai1 介导的 Ca2+ 信号通路作为治疗这种致命疾病的潜在靶点。
Effective treatment as well as prognostic biomarker for malignant esophageal squamous cell carcinoma (ESCC) is urgently needed. The present study was aimed at identifying oncogenic genes involving dysregulated intracellular Ca2+ signaling, which is known to function importantly in cellular proliferation and migration. Tumors from patients with ESCC were found to display elevated expression of Orai1, a store-operated Ca2+ entry (SOCE) channel, and the high expression of Orai1 was associated with poor overall and recurrence-free survival. In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing. Moreover, pharmacologic inhibition of Orai1 activity or reduction of Orai1 expression suppressed proliferation and migration of ESCC in vitro and slowed tumor formation and growth in in vivo xenografted mice. Combined, these findings provide the first evidence to imply Orai1 as a novel biomarker for ESCC prognostic stratification and also highlight Orai1-mediated Ca2+ signaling pathway as a potential target for treatment of this deadly disease.