QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth
QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth
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DOI：
10.1002/ijc.32372
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发表时间：
2019-09-15
影响因子：
6.4
通讯作者：
Ko, Yoon Ho
中科院分区：
文献类型：
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作者：
Kim, Eun Ju;Kim, Jeong Seon;Ko, Yoon Ho
microRNA-200（miR-200）家族通过阻止转录抑制子ZEB 1和ZEB 2的表达在指定上皮表型中起主要作用，所述转录抑制子ZEB 1和ZEB 2是包括口腔鳞状细胞癌（OSCC）在内的上皮肿瘤中上皮向间质转化（EMT）的众所周知的调节剂。在这里，我们阐明了miR-200家族成员是否控制RNA结合蛋白震颤（QKI），一种新发现的肿瘤抑制因子，在EMT期间受到调节。我们通过TargetScan和The Cancer Genome Atlas头颈部鳞状细胞癌（HNSCC）数据集的分析预测miR-200 a和miR-200 b可以识别QKI 3 '-UTR。miR-200 b/a/429的强制表达抑制了ZEB 1/2的表达，并降低了OSCC细胞系CAL 27和HSC 3的细胞迁移。QKI表达也被miR-200过表达抑制，并且QKI mRNA的3 '-UTR在荧光素酶报告基因测定中被miR-200直接靶向。有趣的是，在OSCC的体外和体内研究中，shRNA介导的QKI敲低导致明显的EMT和促肿瘤作用。此外，QKI蛋白的高表达与手术切除的HNSCC和肺腺癌的良好预后相关。总之，QKI在EMT期间增加，并被miR-200靶向;同时，它抑制EMT和肿瘤发生。我们认为QKI和miR-200形成负反馈环，以维持对EMT诱导信号的稳态反应。
The microRNA-200 (miR-200) family plays a major role in specifying epithelial phenotype by preventing expression of the transcription repressors ZEB1 and ZEB2, which are well-known regulators of the epithelial-to-mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether miR-200 family members control RNA-binding protein quaking (QKI), a newly identified tumor suppressor that is regulated during EMT. We predicted that miR-200a and miR-200b could recognize QKI 3 '-UTR by analyzing TargetScan and The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) dataset. Forced expression of miR-200b/a/429 inhibited expression of ZEB1/2 and decreased cell migration in OSCC cell lines CAL27 and HSC3. QKI expression was also suppressed by miR-200 overexpression, and the 3 '-UTR of QKI mRNA was directly targeted by miR-200 in luciferase reporter assays. Interestingly, shRNA-mediated knockdown of QKI led to pronounced EMT and protumor effects in both in vitro and in vivo studies of OSCC. Furthermore, high expression of QKI protein is associated with favorable prognosis in surgically resected HNSCC and lung adenocarcinoma. In conclusion, QKI increases during EMT and is targeted by miR-200; while, it suppresses EMT and tumorigenesis. We suggest that QKI and miR-200 form a negative feedback loop to maintain homeostatic responses to EMT-inducing signals.