MicroRNA-552 links Wnt signaling to p53 tumor suppressor in colorectal cancer

Abstract

The aberrant expression of microRNAs (miRNAs or miRs) has been shown to be associated with the development of various types of cancer, including colorectal cancer (CRC). The increased activation of the Wnt signaling pathway via the loss of the Wnt repressor, adenomatous polyposis coli (APC), is the hallmark of human CRC. In this study, we demonstrate that the activation of the Wnt/c-Myc axis inhibits the expression of the tumor suppressor, p53, via promoting the targeting of p53 by miR-552. Our results revealed that the ectopic expression of miR-552 enhanced cell proliferation, colony formation and resistance to drug-induced apoptosis, suggesting that this miRNA may function as an oncogene. We found that miR-552 displayed oncogenic properties by directly targeting the p53 tumor suppressor. Of note, our genetic and pharmacological experiments revealed that the Wnt/β-catenin signaling pathway and its major downstream target, c-Myc (hereafter termed Myc), increased the miR-552 levels, and chromatin immunoprecipitation (ChIP) assays revealed they carried out this function by directly binding to their binding sites in the miR-552 promoter region. Given that the functional loss of APC, leading to abnormal Wnt signals, and the absence of p53 protein are common in CRC, these results suggest that miR-552 may serve as an important link between these two events, and this warrants further investigation. Collectively, the data of this study suggest that the inhibition of miR-552 may disconnect elevated Wnt signals from p53 suppression, providing a novel therapeutic strategy for patients with CRC with deregulated Wnt signaling.