title: N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN.
abstract: Cadherin subtype switching from E-cadherin to N-cadherin is associated with the epithelial-to-mesenchymal transition (EMT), a process required for invasion and dissemination of carcinoma cells. We found that N-cadherin is expressed in human and mouse pancreatic intraepithelial neoplasia (PanIN), suggesting that N-cadherin may also have a role in early-stage pancreatic cancer. To investigate the role of N-cadherin in mouse PanIN (mPanIN), we simultaneously activated oncogenic K-ras(G12D) and deleted the N-cadherin (Cdh2) gene in the murine pancreas. Genetic ablation of N-cadherin (N-cad KO) caused hyperproliferation, accelerated mPanIN progression, and early tumor development in K-ras(G12D) mice. Decreased E-cadherin and redistribution of β-catenin accompanied the loss of N-cadherin in pancreatic ductal epithelial cells (PDEC). Nuclear accumulation of β-catenin and its transcription co-activator Tcf4 led to activation of Wnt/β-catenin target genes. Unexpectedly, loss of N-cadherin in the K-ras(G12D) model resulted in increased mPanIN progression and tumor incidence. These in vivo results demonstrate for the first time that N-cadherin functions as a growth suppressor in the context of oncogenic K-ras.
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Departments of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shi
authors.affiliation: Departments of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras)