Abstract
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.
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