Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer.
Adenomatous polyposis coli (APC) regulates miR17-92 cluster through β-catenin pathway in colorectal cancer.
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DOI：
10.1038/onc.2015.522
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发表时间：
2016-09-01
期刊：
影响因子：
8
通讯作者：
Cheng JQ
中科院分区：
文献类型：
--
作者：
Li Y;Lauriola M;Kim D;Francesconi M;D'Uva G;Shibata D;Malafa MP;Yeatman TJ;Coppola D;Solmi R;Cheng JQ
APC突变是散发性结直肠癌（CRC）中最常见的基因改变。尽管在这种恶性肿瘤中经常报道miRNA的失调，但APC调节的miRNA尚未被广泛记录。在这里，通过采用APC诱导型细胞系和阵列分析，我们鉴定了总共26种失调的miRNA。其中miR-17-92簇的成员被APC显著抑制并被β-catenin的增强表达诱导。此外，我们证明了APC缺失导致的活化β-连环蛋白结合并活化miR-17-92启动子。值得注意的是，miR-19 a的强制表达超过了APC肿瘤抑制活性，并且在APC功能受损的癌细胞中敲低miR-19 a降低了其体外侵袭性特征。最后，我们观察到miR-19 a的表达与结直肠癌标本中的β-catenin水平显著相关，并且与肿瘤进展的侵袭性阶段相关。因此，我们的研究表明，miR-17-92簇受APC/β-catenin信号通路的直接调控，可能成为APC/β-catenin信号通路异常的结肠癌潜在治疗靶点。
APC mutation is the most common genetic changes in sporadic colorectal cancer (CRC). Despite deregulations of miRNAs have been frequently reported in this malignancy, APC regulated miRNAs have not been extensively documented. Here, by employing an APC inducible cell line and array analysis, we identified a total of 26 deregulated miRNAs. Among them members of miR-17-92 cluster were dramatically inhibited by APC and induced by enforced expression of β-catenin. Furthermore, we demonstrate that activated β-catenin resulted from APC loss binds to and activates the miR-17-92 promoter. Notably, enforced expression of miR-19a overrides APC tumour suppressor activity and knockdown of miR-19a in cancer cells with compromised APC function reduced their aggressive features in vitro. Finally, we observed that expression of miR-19a significantly correlates with β-catenin levels in colorectal cancer specimens, and it is associated to the aggressive stage of tumour progression. Thus our study reveals that miR-17-92 cluster is directly regulated by APC/β-catenin pathway and could be a potential therapeutic target in colon cancers with aberrant APC/β-catenin signaling.