Neuromedin U contributes to radiation resistance in colorectal cancer via YAP/TAZ signaling activation

초록

Resistance to radiation therapy remains a treatment obstacle for patients with high-risk colorectal cancer. Neuromedin U (NMU) has been identified as a potential predictor of the response to radiation therapy by RNA sequencing analysis of colorectal cancer tissues obtained from patients. However, the role of NMU in colorectal cancer remains unknown. In order to investigate role of NMU in colorectal cancer, NMU expression was regulated using small interfering RNA or an NMU-expression pCMV3 vector, and cell counting, wound-healing and clonogenic assays were subsequently performed. NMU knockdown decreased colorectal cancer cell proliferation and migration, and sensitized the cells to radiation. Conversely, NMU overexpression increased radiation resistance, proliferation and migration of colorectal cancer cells. Furthermore, by western blotting and nuclear fractionation experiments, NMU knockdown inhibited the nuclear translocation of yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), resulting from the phosphorylation of these proteins. By contrast, the nuclear translocation of YAP and TAZ was increased following NMU overexpression in colorectal cancer cells. Recombinant NMU regulated YAP and TAZ activity, and the expression of the YAP and TAZ transcriptional target genes AXL, connective tissue growth factor and cysteine-rich angiogenic inducer 61 in an NMU receptor 1 activity-dependent manner. These results suggested that NMU may contribute to the acquisition of radioresistance in colorectal cancer by enhancing the Hippo signaling pathway via YAP and TAZ activation.

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