Urocortin-1 Promotes Colorectal Cancer Cells Migration, Proliferation and Inhibits Apoptosis via Inhibition of p53 Signaling Pathway

Abstract

Abstract Purpose To investigate the effect of urocortin-1 (UCN-1) on the growth, migration and apoptosis of colorectal cancer (CRC) in vivo and vitro and mechanism of UCN-1 modulating CRC cells in vitro. Methods The correlation between UCN-1 and CRC was evaluated by Cancer Genome Atlas (TCGA) database and the tissues microarray. The expression of UCN-1 in CRC cells was explored by quantitative real-time polymerase chain reaction (RT-qPCR) or western blot. In vitro, the influence of UCN-1 on proliferation, apoptosis and migration HCT-116 and RKO cells were explored by celigo cell counting assay, flow cytometry and wound healing assay or transwell, respectively. In vivo the effect of UCN-1 on CRC tumor growth and progression was evaluated in the nude mice. The downstream pathway behind UCN-1 regulating CRC was found by phospho-kinase profiler array in RKO cells. Expression of UCN-1 in cells was knocked down or upregulated using lentivirus. Results Both of the results of TCGA database and the tissues microarray shown that UCN-1 strongly expressed in tissues of CRC patients. Furthermore, the tissues microarray results showed that expression of UCN-1 was higher in male CRC patients than that in female patients, and high expression of UCN-1 was associated with higher risk of lymphatic metastasis and later pathological stage. Additionally, knockdown of UCN-1 in CRC cells caused a reduction in cell proliferation, migration, and colony formation as well as an increase in apoptosis. In xenograft experiments, tumors generated from RKO cells with UCN-1 knockdown exhibited declined tumor volume and weight. Reduction of the expression of Ki67 in xenograft tumors reflected that knockdown of UCN-1 curbed the growth of CRC tumors. Furthermore, the human phospho-kinase array showed that p53 signal pathway participated in UCN-1-mediated CRC development. The suppression in migration and proliferation caused by UCN-1 knockdown was reversed by inhibitors of p53 signal pathway, while the increase of cell apoptosis was withdrawn. On the other hand, overexpression of UCN-1 promoted the proliferation and migration and inhibited apoptosis of CRC cells. Overexpression of p53 reversed the effect of UCN-1 overexpression on CRC development. Conclusion UCN-1 promotes the migration, proliferation and inhibits apoptosis via inhibition of p53 signaling pathways.