MiRNA-194 activates the Wnt/β-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU
MiRNA-194 activates the Wnt/β-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU
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MiRNA-194 通过靶向 Wnt 负调节因子 SUFU 激活胃癌中的 Wnt/β-catenin 信号通路。
DOI：
10.1016/j.canlet.2016.10.035
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发表时间：
2017-01-28
期刊：
影响因子：
9.7
通讯作者：
Meltzer, Stephen J.
中科院分区：
文献类型：
--
作者：
Peng, Yin;Zhang, Xiaojing;Meltzer, Stephen J.
新的证据表明，miRNA-194在胃癌中异常上调；然而，其参与的生物学机制很大程度上是未知的。Wnt/β-catenin信号与胃癌的发生有关，因此我们假设miRNA-194通过激活Wnt/β-catenin信号促进胃癌的发生。研究发现，miRNA-194在胃癌细胞系和43对胃癌组织中高表达。MiRNA-194的过表达促进了细胞的增殖和迁移，而抑制miRNA-194则阻止了这些过程。抑制miRNA-194可减少裸鼠体内的肿瘤体积。此外，miRNA-194抑制剂促进β-连环蛋白的细胞质定位，从而抑制Wnt信号转导。我们还发现，已知的Hedgehog和Wnt信号的负调控因子SuFU是miRNA-194的靶标。抗SuFU siRNAs可拮抗miRNA-194拮抗剂对细胞增殖、迁移和克隆形成的抑制作用。我们还发现SuFU在胃癌组织和细胞系中的表达下调，并与原代胃癌组织中miRNA-194的表达呈负相关。此外，SUFU的表达与肿瘤分期呈负相关，支持其作为胃癌诊断或预后标志物的可能性。综上所述，这些发现表明miRNA-194是致癌的，通过激活Wnt信号促进GC细胞的增殖和迁移，至少部分是通过抑制SuFU。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Emerging evidence has shown that miRNA-194 is aberrantly upregulated in gastric cancer (GC); however, the biological mechanisms underlying its involvement are largely unknown. Wnt/beta-catenin signaling has been implicated in gastric tumorigenesis; we therefore hypothesized that miRNA-194 promotes gastric carcinogenesis by activating Wnt/beta-catenin signaling. MiRNA-194 was found to be overexpressed in GC cell lines and 43 paired GC tissues. Overexpression of miRNA-194 promoted cell proliferation and migration, while inhibition of miRNA-194 blocked these processes. Inhibition of miRNA-194 decreased tumor volumes in nude mice. Furthermore, miRNA-194 inhibitors promoted cytoplasmic localization of beta-catenin, leading to repression of Wnt signaling. We also discovered that SUFU, a known negative regulator of Hedgehog and Wnt signaling, was a target of miRNA-194. Anti-SUFU siRNAs rescued the inhibitory effects of miRNA-194 antagonists on cell proliferation and migration and on colony formation. We also found that SUFU expression was downregulated in GC tissues and cell lines and negatively correlated with miRNA-194 expression in primary GC tissues. Moreover, SUFU expression was negatively correlated with tumor stage, supporting its potential as a diagnostic or prognostic marker in GC. Taken together, these findings suggest that miRNA-194 is oncogenic and promotes GC cell proliferation and migration by activating Wnt signaling, at least in part, via suppression of SUFU. (C) 2016 Elsevier Ireland Ltd. All rights reserved.