MiR-452 promotes an aggressive colorectal cancer phenotype by regulating a Wnt/β-catenin positive feedback loop.
MiR-452 promotes an aggressive colorectal cancer phenotype by regulating a Wnt/β-catenin positive feedback loop.
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MiR-452 通过调节 Wnt/β-连环蛋白正反馈环促进侵袭性结直肠癌表型
DOI：
10.1186/s13046-018-0879-z
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发表时间：
2018-09-25
期刊：
影响因子：
--
通讯作者：
Ding Y
中科院分区：
文献类型：
--
作者：
Li T;Jian X;He H;Lai Q;Li X;Deng D;Liu T;Zhu J;Jiao H;Ye Y;Wang S;Yang M;Zheng L;Zhou W;Ding Y
Wnt/β-catenin信号通路的异常激活被认为是多种人类癌症，尤其是结直肠癌（CRC）进展和转移的重要问题。miR-452可激活Wnt/β-catenin信号通路。但其机制仍不清楚。采用实时荧光定量PCR方法检测miR-452在结直肠癌组织和正常组织中的表达。通过体外和体内功能实验研究miR-452对结直肠癌生长和侵袭的影响。生物信息学和细胞荧光素酶功能研究证实了miR-452对GSK 3 β的3 '-UTR的直接调控，从而导致Wnt/β-catenin信号通路的激活。与正常组织相比，miR-452在CRC中上调，并且与临床意义相关。荧光素酶报告系统研究证实了miR-452对GSK 3 β的3 '-UTR的直接调节，其激活Wnt/β-catenin信号传导。miR-452的异位上调可显著抑制GSK 3 β的表达，增强结直肠癌的体外和体内增殖和侵袭。同时，下调miR-452可显著恢复GSK 3 β的表达，抑制Wnt/β-catenin介导的细胞转移和增殖。更重要的是，作为Wnt/β-catenin信号通路的关键下游分子的T细胞因子/淋巴增强因子（TCF/LEF）家族转录因子被证实是miR-452启动子的有效转录因子。我们的研究结果首次证明miR-452-GSK 3 β-LEF 1/TCF 4正反馈环诱导CRC增殖和迁移。本文的在线版本（10.1186/s13046-018-0879-z）包含补充材料，可供授权用户使用。
Aberrant activation of Wnt/β-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/β-catenin signaling. But the mechanism remains unclear. The expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3’-UTR of the GSK3β, which leads to the activation of Wnt/β-catenin signaling. MiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3’-UTR of the GSK3β, which activate the Wnt/β-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3β and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3β and attenuated Wnt/β-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/β-catenin signaling pathway was verified as a valid transcription factor of miR-452’s promoter. Our findings first demonstrate that miR-452-GSK3β-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration. The online version of this article (10.1186/s13046-018-0879-z) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
Lin CY;Tzeng HE;Li TM;Chen HT;Lee Y;Yang YC;Wang SW;Yang WH;Tang CH
通讯作者：
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6.4
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通讯作者：
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