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-rasG12D 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-rasG12D 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-rasG12D 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.
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Acknowledgements
We are grateful to Frans van Roy, Anil Rustgi and Jennifer Wilson for comments. We thank David Tuveson for the LSL-K-rasG12D mice, Andrew Lowy for the Pdx1/Cre mice and Michael Goggins for the PanIN microarrays. We are grateful to Mathew Thakur for assistance with PET imaging, and Han Du, Craig Riley and David Kurz for technical assistance. Research in this study includes work carried out by the Jefferson Kimmel Cancer Center Small Animal Imaging Facility, which is supported in part by NCI Cancer Center Support Grant P30 CA56036. This work was supported by NIH R21 CA176097 (GR). This study was also supported by the SPORE grant CA62924 (RH).
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Su, Y., Li, J., Shi, C. et al. N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN. Oncogene 35, 3335–3341 (2016). https://doi.org/10.1038/onc.2015.382
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DOI: https://doi.org/10.1038/onc.2015.382
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