Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia

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-alpha) or K-ras(G12D) in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCi) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCi expression was assessed in a mouse model of K-ras(G12D)-induced pancreatic ADM and pancreatic cancer. The ability of K-ras(G12D) to induce pancreatic ADM in explant culture, and the requirement for PKCi, was investigated. PKCi is elevated in human and mouse pancreatic ADM and intraepithelial neoplastic lesions in vivo. We demonstrate that K-ras(G12D) is sufficient to induce pancreatic ADM in explant culture, exhibiting many of the same morphologic and biochemical alterations observed in TGF-alpha-induced ADM, including a dependence on Notch activation. PKCi is highly expressed in both TGF-alpha- and K-ras(G12D)-induced pancreatic ADM and inhibition of PKCi significantly reduces TGF-alpha- and K-ras(G12D)-mediated ADM. Inhibition of PKCi suppresses K-ras(G12D)-induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-ras(G12D)-mediated ADM in PKCi-depleted cells, implicating a K-ras(G12D)-PKCi-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCi is an early marker of pancreatic neoplasia and suggest that PKCi is a potential downstream target of K-ras(G12D) in pancreatic ductal metaplasia in vivo.