Journal
CANCER LETTERS
Volume 375, Issue 1, Pages 179-189Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.02.049
Keywords
Nectin-4; Tumor progression; Gallbladder cancer; PI3K/AKT pathway; Rac1
Categories
Funding
- National Natural Science Foundation of China [81172026, 81272402, 81301816, 81172029, 91440203, 81402403, 31501127]
- National High Technology Research and Development Program (863 Program) [2012AA022606]
- Foundation for Interdisciplinary Research of Shanghai Jiao Tong University [YG2011ZD07]
- Shanghai Science and Technology Commission Intergovernmental International Cooperation Project [12410705900]
- Shanghai Science and Technology Commission Medical Guiding Project [12401905800]
- Program for Changjiang Scholars
- Natural Science Research Foundation of Shanghai Jiao Tong University School of Medicine [13XJ10037]
- Leading Talent program of Shanghai
- Specialized Research Foundation for the PhD Program of Higher Education-Priority Development Field [20130073130014]
- Interdisciplinary Program of Shanghai Jiao Tong University [14JCRY05]
- Shanghai Rising-Star Program [15QA1403100]
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Nectin-4 is a Ca2+-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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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