MOR promotes epithelial-mesenchymal transition and proliferation via PI3K/AKT signaling pathway in human colorectal cancer

The mu-opioid receptor (MOR), a membrane-bound G protein-coupled receptor, is implicated in progression and long-term outcome of several types of tumors. However, the expression and clinical significance of MOR in colorectal cancer (CRC) remain unclear. In this study, a total of 180 paraffin-embedded samples of paired tumors and normal tissues from CRC patients are used to explore expression levels of MOR by immunohistochemistry (IHC). Results show that MOR is highly expressed in tumors compared with that in paired normal tissues ( P<0.0001). MOR expression levels are associated with the degree of differentiation ( P<0.001) and the regional lymph node metastasis ( P<0.001). In addition, a significant difference is also found in the overall survival (OS) between MOR low- and high-expression groups ( P=0.002), especially in patients with TNM stage III or IV CRC ( P=0.007). Both univariate ( P=0.002) and multivariate ( P=0.013) analyses indicated that MOR is an independent risk factor associated with CRC prognosis. We further investigate the mechanism in MOR-positive CRC cell line HCT116. The results show that silencing of MOR significantly suppresses epithelial-mesenchymal transition (EMT), in addition to suppressing cell proliferation, migration, and invasion. In addition, the expression of downstream p-AKT is also significantly downregulated, and the above suppression effect could be rescued by PI3K/AKT signaling agonist. We conclude that MOR mediates EMT via PI3K/AKT signaling, facilitating lymph node metastasis and resulting in poor survival of CRC patients. Our findings suggest that MOR is a novel prognostic indicator and the application of opioid receptor antagonists may be a novel therapeutic strategy for CRC patients with high MOR expression.