Pancreatic acinar-to-ductal metaplasia (ADM) is associated with an increased risk of pancreatic cancer and is considered a precursor of pancreatic ductal adenocarcinoma. Transgenic expression of transforming growth factor alpha (TGF-a) or K-rasG12D in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKC¿) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKC¿ expression was assessed in a mouse model of K-rasG12D-induced pancreatic ADM and pancreatic cancer. The ability of K-rasG12D to induce pancreatic ADM in explant culture, and the requirement for PKC¿, was investigated. PKC¿ is elevated in human and mouse pancreatic ADM and intraepithelial neoplastic lesions in vivo. We demonstrate that K-rasG12D is sufficient to induce pancreatic ADM in explant culture, exhibiting many of the same morphologic and biochemical alterations observed in TGF-a-induced ADM, including a dependence on Notch activation. PKC¿ is highly expressed in both TGF-a- and K-rasG12D-induced pancreatic ADM and inhibition of PKC¿ significantly reduces TGF-a- and K-rasG12D-mediated ADM. Inhibition of PKC¿ suppresses K-rasG12D–induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-rasG12D–mediated ADM in PKC¿-depleted cells, implicating a K-rasG12D-PKC¿-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKC¿ is an early marker of pancreatic neoplasia and suggest that PKC¿ is a potential downstream target of K-rasG12D in pancreatic ductal metaplasia in vivo.

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