N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN.
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.
Duke Scholars
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Related Subject Headings
- beta Catenin
- Wnt Signaling Pathway
- Proto-Oncogene Proteins p21(ras)
- Precancerous Conditions
- Pancreatic Neoplasms
- Pancreas
- Oncology & Carcinogenesis
- Mice, Transgenic
- Mice, Knockout
- Immunohistochemistry
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta Catenin
- Wnt Signaling Pathway
- Proto-Oncogene Proteins p21(ras)
- Precancerous Conditions
- Pancreatic Neoplasms
- Pancreas
- Oncology & Carcinogenesis
- Mice, Transgenic
- Mice, Knockout
- Immunohistochemistry