MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer.
MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer.
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MicroRNA-224维持Wnt/β-catenin信号传导并促进结直肠癌的侵袭性表型
DOI：
10.1186/s13046-016-0287-1
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发表时间：
2016-01-29
期刊：
影响因子：
--
通讯作者：
Liao W
中科院分区：
文献类型：
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作者：
Li T;Lai Q;Wang S;Cai J;Xiao Z;Deng D;He L;Jiao H;Ye Y;Liang L;Ding Y;Liao W
越来越多的证据表明Wnt/β-catenin通路在结直肠癌的发生、发展和转移中起重要作用。在CRC中已经报道了异常的miR-224表达。然而，miR-224促进增殖和转移能力的机制在很大程度上仍不清楚。使用实时PCR定量miR-224表达。荧光素酶报告基因检测证实Wnt/β-catenin通路的活性及靶基因的关联，免疫荧光染色观察β-catenin的核转位。生物信息学分析结合体内外功能检测显示miR-224的潜在靶基因为GSK 3 β和SFRP 2。采用实时荧光定量PCR和Western blot方法检测40例结直肠癌组织中miR-224的表达及其与GSK 3 β/SFRP 2的关系。生物信息学和细胞荧光素酶功能研究证实了miR-224对GSK 3 β和SFRP 2基因的3 '-UTR的直接调控，导致Wnt/β-catenin信号通路的激活和β-catenin的核转位。此外，敲低miR-224显著恢复了GSK 3 β和SFRP 2的表达，并减弱了Wnt/β-catenin介导的细胞转移和增殖。miR-224的异位上调显著抑制了GSK 3 β/SFRP 2的表达，并增强了CRC的增殖和侵袭。我们的研究表明，miR-224和Wnt/β-catenin之间通过调节GSK 3 β和SFRP 2在CRC发病机制中存在机制联系。本文的在线版本（doi：10.1186/s13046-016-0287-1）包含补充材料，可供授权用户使用。
Growing evidence suggests that Wnt/β-catenin pathway plays an important role in CRC development, progression and metastasis. Aberrant miR-224 expression has been reported in CRC. However, the mechanism of miR-224 promotes both proliferation and metastatic ability largely remains unclear. Real-time PCR was used to quantify miR-224 expression. Luciferase reporter assays were conducted to confirm the activity of Wnt/β-catenin pathway and target gene associations, and immunofluorescence staining assay was performed to observe the nuclear translocation of β-catenin. Bioinformatics analysis combined with in vivo and vitro functional assays showed the potential target genes, GSK3β and SFRP2, of miR-224. Specimens from forty patients with CRC were analyzed for the expression of miR-224 and the relationship with GSK3β/SFRP2 by real-time PCR and western blot. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-224 on the 3’-UTR of the GSK3β and SFRP2 genes, which leads to the activation of Wnt/β-catenin signaling and the nuclear translocation of β-catenin. In addition, knockdown of miR-224 significantly recovered the expression of GSK3β and SFRP2 and attenuated Wnt/β-catenin-mediated cell metastasis and proliferation. The ectopic upregulation of miR-224 dramatically inhibited the expression of GSK3β/SFRP2 and enhanced CRC proliferation and invasion. Our research showed mechanistic links between miR-224 and Wnt/β-catenin in the pathogenesis of CRC through modulation of GSK3β and SFRP2. The online version of this article (doi:10.1186/s13046-016-0287-1) contains supplementary material, which is available to authorized users.