Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell-like Phenotype via Dysregulation of PITX2
Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell-like Phenotype via Dysregulation of PITX2
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DOI：
10.1158/1078-0432.ccr-16-0414
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发表时间：
2017-01-01
影响因子：
11.5
通讯作者：
Xie, Dan
中科院分区：
文献类型：
--
作者：
Zhang, Jia-Xing;Chen, Zhen-Hua;Xie, Dan
目的：我们先前报道了配对样同源结构域2（PITX 2）在食管鳞状细胞癌（ESCC）中的致癌作用。本研究的目的是寻找PITX 2的miRNA调控因子，并探讨其在ESCC发病中的作用机制。实验设计：通过miRNA表达谱分析和生物信息学分析，确定miR-644 a是PITX 2在ESCC中的负性调节因子。结果：miR-644 a在食管鳞癌细胞和组织中的表达低于正常上皮细胞，miR-644 a在食管鳞癌中的表达低于正常上皮细胞和组织。在患者样本中，miR-644 a在ESCC组织中的低表达与肿瘤复发和/或转移显著相关，使得miR-644 a、PITX 2以及两者的组合是ESCC患者生存的独立预后指标（P < 0.05）。功能获得和丧失研究表明，miR-644 a在体外抑制ESCC细胞生长、迁移和侵袭，在体内抑制肿瘤生长和转移。此外，miR-644 a显著抑制ESCC细胞的自我更新和干细胞样特征。此外，miR-644 a上调的效果与ESCC细胞中PITX 2敲低的效果相似。机制研究显示，miR-644 a至少部分地通过PITX 2使Akt/GSK-3 β/β-连环蛋白信号通路失活而减弱ESCC细胞的恶性肿瘤和干细胞相关表型。结论：miR-644 a的下调在促进ESCC细胞的侵袭性和干细胞样特征中起重要作用，提示miR-644 a可能作为ESCC的新的预后生物标志物或治疗靶点。(C)2016年AACR。
Purpose: We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain-and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3 beta/beta-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. (C) 2016 AACR.