MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC

• Published in: Oncotarget Vol. 6; no. 32; pp. 33805 - 33822
• Main Authors: Wang, Linjun, Zhi, Xiaofei, Zhu, Yi, Zhang, Qun, Wang, Weizhi, Li, Zheng, Tang, Jie, Wang, Jiwei, Wei, Song, Li, Bowen, Zhou, Jianping, Jiang, Jianguo, Yang, Li, Xu, Hao, Xu, Zekuan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20-10-2015
• Subjects: Animals; Axons - metabolism; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Movement; Coculture Techniques; Focal Adhesion Kinase 1 - metabolism; Ganglia, Spinal - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 8 - metabolism; Mucin-4 - metabolism; Neoplasm Invasiveness; Nerve Growth Factors - metabolism; Netrin-1; Neurons - pathology; NF-kappa B p50 Subunit - metabolism; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - metabolism; Research Paper; RNA Interference; src-Family Kinases - metabolism; Tumor Suppressor Proteins - metabolism; Netrin-1; MUC4; neural invasion; pancreatic ductal adenocarcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5668

Neural invasion (NI) is an important oncological feature of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism of NI in PDAC remains unclear. In this study, we found that MUC4 was overexpressed in PDAC tissues and high expression of MUC4 indicated a higher NI incidence than low expression. In vitro, MUC4 knockdown inhibited the migration and invasion of PDAC cells and impaired the migration of PDAC cells along nerve in dorsal root ganglia (DRG)-PDAC cell co-culture assay. In vivo, MUC4 knockdown suppressed the NI of PDAC cells in a murine NI model. Mechanistically, our data revealed that MUC4 silencing resulted in decreased netrin-1 expression and re-expression of netrin-1 in MUC4-silenced cells rescued the capability of NI. Furthermore, we identified that decreased netrin-1 expression was owed to the downregulation of HER2/AKT/NF-κB pathway in MUC4-silenced cells. Additionally, MUC4 knockdown also resulted in the downregulation of pFAK, pSrc, pJNK and MMP9. Taken together, our findings revealed a novel role of MUC4 in potentiating NI via netrin-1 through the HER2/AKT/NF-κB pathway in PDAC.