title: MUC4-promoted neural invasion is mediated by the axon guidance factor Netrin-1 in PDAC.
abstract: 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.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Linjun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Weizhi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gastrointestinal Surgery, Taizhou People's Hospital, Taizhou, Jiangsu, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.|Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
authors.forename: Zekuan
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D055264:Mucin-4 / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D009474:Neurons / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051417:Focal Adhesion Kinase 1; D020780:Matrix Metalloproteinase 9; D048055:Mitogen-Activated Protein Kinase 8; D055264:Mucin-4; D052002:NF-kappa B p50 Subunit; D009414:Nerve Growth Factors; D000075388:Netrin-1; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases; C524658:MUC4 protein, human; C489548:NFKB1 protein, human; C000617351:NTN1 protein, human; C000617353:Ntn1 protein, mouse; C508053:ERBB2 protein, human; C496050:PTK2 protein, human; C494918:AKT1 protein, human; C579270:MMP9 protein, human
keywords: MUC4; Netrin-1; neural invasion; pancreatic ductal adenocarcinoma