Involvement of aberrant miR-139/Jun feedback loop in human gastric cancer.
Involvement of aberrant miR-139/Jun feedback loop in human gastric cancer.
复制标题
异常 miR-139/Jun 反馈环路与人胃癌的关系。
DOI：
10.1016/j.bbamcr.2014.12.002
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Zhao, Zhi-Hu
中科院分区：
文献类型：
--
作者：
Zhang, Le-Zhi;Zhang, Zhang;Li, Ping;Xing, Ling-Yue;Luo, Feng-Yan;Sun, Qiang;Zheng, Xiao-Fei;Yang, Xiao;Zhao, Zhi-Hu
越来越多的证据表明，一些miRNA可以与其靶点形成反馈环，以微调组织的稳态，而这些环的破坏构成了人类肿瘤发生的重要步骤。在这项研究中，我们发现了一个新的负反馈环，该环在miR-139和其致癌靶点Jun之间形成。在这个环中，miR-139可以通过靶向其3′-UTR上的保守位点抑制Jun的表达，而Jun可以通过一个远距离的上游调控元件以剂量依赖的方式诱导miR-139的表达。有趣的是，在人类胃癌中发现了该环的畸变，其中miR-139下调并与Jun表达呈负相关。进一步的功能分析表明，miR-139在胃癌细胞中的恢复表达通过靶向Jun显著诱导细胞凋亡，抑制细胞迁移和增殖以及肿瘤生长。因此，我们的数据强烈提示了异常的miR-139/Jun负反馈环在人胃癌的发展中的作用，miR-139是胃癌潜在的治疗靶点。鉴于miR-139和Jun在许多癌症中被失调，我们的发现可能对其他类型的人类癌症有更广泛的意义。
Accumulating evidence indicates that some miRNAs could form feedback loops with their targets to fine-tune tissue homeostasis, while disruption of these loops constitutes an essential step towards human tumorigenesis. In this study, we report the identification of a novel negative feedback loop formed between miR-139 and its oncogenic target Jun. In this loop, miR-139 could inhibit Jun expression by targeting a conserved site on its 3′-UTR, whereas Jun could induce miR-139 expression in a dose dependent manner through a distant upstream regulatory element. Interestingly, aberration in this loop was found in human gastric cancer, where miR-139 was down-regulated and inversely correlated with Jun expression. Further functional analysis showed that restored expression of miR-139 in gastric cancer cells significantly induces apoptosis, and inhibits cell migration and proliferation as well as tumour growth through targeting Jun. Thus, our data strongly suggests a role of aberrant miR-139/Jun negative feedback loop in the development of human gastric cancer and miR-139 as a potential therapeutic target for gastric cancer. Given that miR-139 and Jun are deregulated in many cancers, our findings here might have broader implication in other types of human cancers.
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