title: A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth.
abstract: Nectin-4 is a Ca(2+)-independent immunoglobulin-like cell adhesion molecule which has diverse functions in cell-cell adhesion via homophilic and heterophilic interactions. Cell-cell adhesive processes are central to cell polarization, differentiation, proliferation, survival and movement. Here we report that Nectin-4 is substantially overexpressed in gallbladder cancer (GBC), the most common biliary tract malignancy with a high risk of local tumor spread and invasion. Further, Nectin-4 high expression in GBC patients was associated with pathologic T stage and lymph node metastasis status, and the expression level of the downstream target Rac1 and poor prognoses were also correlated with Nectin-4. Ectopic expression of Nectin-4 promoted GBC cell growth, motility and tumor growth in a mouse model. The depletion of Nectin-4 inhibited GBC cell proliferation and migration both in cell culture and in mice. Our data suggest that activation of the PI3K/AKT pathway was involved in the oncogenic function of Nectin-4 to activate Rac1 in GBC. Inhibition of PI3K/AKT with LY294002 and/or Rac1 with NSC23766 impaired Nectin-4-mediated GBC cell proliferation and motility. We hypothesize that Nectin-4 is critical for GBC progression via PI3K/AKT pathway activation of Rac1. Nectin-4 may be a novel prognostic factor and therapeutic target in GBC patients.
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Yijian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, China.
authors.forename: Yaoshi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Xu-An
authors.initials: XA
authors.lastname: Wang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Huaifeng
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Runfa
authors.initials: R
authors.lastname: Bao
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Electronic address: fcyc6110@126.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. Electronic address: liuybphd@126.com.
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000075983:Nectins
chemical_list: D015815:Cell Adhesion Molecules; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; C107953:RAC1 protein, human; C442228:NECTIN4 protein, human; D000075983:Nectins
keywords: Gallbladder cancer; Nectin-4; PI3K/AKT pathway; Rac1; Tumor progression