Netrin-1-UNC5B/neogenin axis enhances the stemness of colorectal cancer cells

Cancer stem cells were prominent responsible for cancer initiation, metastasis, and invasion as well as therapeutic resistance in colorectal cancer (CRC). The extracellular axon guidance factor netrin-1 has been found to be overexpressed in several malignant cancers such as glioma, lung cancers, and colorectal cancer. However, the role of netrin-1 on cancer stemness in CRC remains unveiled. Our study revealed high expression of netrin-1 in colorectal cancer tissues and its ability to promote cancer stemness by interacting with receptors UNC5B and neogenin on murine colorectal cancer cell. Mechanistically, the netrin-1-UNC5B/neogenin axis activates the downstream NF-κB and ERK1/2 signaling pathways, reinforcing the stemness properties of tumor cells, and further exacerbating tumor progression. Clinically, netrin-1 expression associated with poor survival and high CD133 expression in patients with CRC. Taken together, these results suggest that netrin-1 blockade could be a compelling therapeutic strategy to improve the poor outcomes and trigger cancer stemness inhibition in CRC treatment.