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

  • Cell Commun Signal. 2025 Nov 13;23(1):496. doi: 10.1186/s12964-025-02489-1.
Xueli Xia  1  2 ,  Zhenwei Mao  2  3 ,  Wenxin Wang  1 ,  Lin Zhao  1  2 ,  Mengxue Xu  3 ,  Jie Ma  2 ,  Jie Tian  2 ,  Kai Yin  4 ,  Shengjun Wang  5  6
Affiliations
  • 1. Department of Laboratory Medicine, Jiangsu Province Engineering Research Center for Precise Diagnosis and Treatment of Inflammatory Diseases, Affiliated Hospital, Jiangsu University, Jiefang Road No 438, Zhenjiang, 212001, China.
  • 2. Department of Immunology, Jiangsu University School of Medicine, Zhenjiang , 212013, China.
  • 3. Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang , 212002, China.
  • 4. Department of General Surgery, Affiliated Hospital of Jiangsu University, Institute of Digestive Diseases, Jiangsu University, Jiefang Road No 438, Zhenjiang, 212001, China. [email protected].
  • 5. Department of Laboratory Medicine, Jiangsu Province Engineering Research Center for Precise Diagnosis and Treatment of Inflammatory Diseases, Affiliated Hospital, Jiangsu University, Jiefang Road No 438, Zhenjiang, 212001, China. [email protected].
  • 6. Department of Immunology, Jiangsu University School of Medicine, Zhenjiang , 212013, China. [email protected].
PMID: 41233873 DOI: 10.1186/s12964-025-02489-1
Abstract

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.

Keywords
Cancer stemness; Colorectal cancer; ERK1/2; NF-κB; Neogenin; Netrin-1; UNC5B.
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