MUC4-promoted neural invasion is mediated by the axon guidance factor netrin-1 in PDAC
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Linjun Wang1,*, Xiaofei Zhi2,*, Yi Zhu1,*, Qun Zhang1, Weizhi Wang1, Zheng Li1, Jie Tang1, Jiwei Wang1, Song Wei1, Bowen Li1, Jianping Zhou3, Jianguo Jiang4, Li Yang1, Hao Xu1 and Zekuan Xu1,5
1 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
2 Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
3 Department of Gastrointestinal Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, P.R. China
4 Department of Gastrointestinal Surgery, Taizhou People’s Hospital, Taizhou, Jiangsu, P.R. China
5 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
* These authors have contributed equally to this work
Zekuan Xu, email:
Keywords: MUC4; neural invasion; pancreatic ductal adenocarcinoma; netrin-1
Received: April 15, 2015 Accepted: August 26, 2015 Published: September 15, 2015
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.
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