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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-α) or K-ras(G12D) in mouse pancreatic epithelium induces ADM in viv...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281025/ https://www.ncbi.nlm.nih.gov/pubmed/22359542 http://dx.doi.org/10.1371/journal.pone.0030509 |
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author | Scotti, Michele L. Smith, Kristin E. Butler, Amanda M. Calcagno, Shelly R. Crawford, Howard C. Leitges, Michael Fields, Alan P. Murray, Nicole R. |
author_facet | Scotti, Michele L. Smith, Kristin E. Butler, Amanda M. Calcagno, Shelly R. Crawford, Howard C. Leitges, Michael Fields, Alan P. Murray, Nicole R. |
author_sort | Scotti, Michele L. |
collection | PubMed |
description | 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-α) or K-ras(G12D) in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCι) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCι 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 PKCι, was investigated. PKCι 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-α-induced ADM, including a dependence on Notch activation. PKCι is highly expressed in both TGF-α- and K-ras(G12D)-induced pancreatic ADM and inhibition of PKCι significantly reduces TGF-α- and K-ras(G12D)-mediated ADM. Inhibition of PKCι suppresses K-ras(G12D)–induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-ras(G12D)–mediated ADM in PKCι-depleted cells, implicating a K-ras(G12D)-PKCι-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCι is an early marker of pancreatic neoplasia and suggest that PKCι is a potential downstream target of K-ras(G12D) in pancreatic ductal metaplasia in vivo. |
format | Online Article Text |
id | pubmed-3281025 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32810252012-02-22 Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia Scotti, Michele L. Smith, Kristin E. Butler, Amanda M. Calcagno, Shelly R. Crawford, Howard C. Leitges, Michael Fields, Alan P. Murray, Nicole R. PLoS One Research Article 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-α) or K-ras(G12D) in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCι) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCι 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 PKCι, was investigated. PKCι 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-α-induced ADM, including a dependence on Notch activation. PKCι is highly expressed in both TGF-α- and K-ras(G12D)-induced pancreatic ADM and inhibition of PKCι significantly reduces TGF-α- and K-ras(G12D)-mediated ADM. Inhibition of PKCι suppresses K-ras(G12D)–induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-ras(G12D)–mediated ADM in PKCι-depleted cells, implicating a K-ras(G12D)-PKCι-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCι is an early marker of pancreatic neoplasia and suggest that PKCι is a potential downstream target of K-ras(G12D) in pancreatic ductal metaplasia in vivo. Public Library of Science 2012-02-16 /pmc/articles/PMC3281025/ /pubmed/22359542 http://dx.doi.org/10.1371/journal.pone.0030509 Text en Scotti et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Scotti, Michele L. Smith, Kristin E. Butler, Amanda M. Calcagno, Shelly R. Crawford, Howard C. Leitges, Michael Fields, Alan P. Murray, Nicole R. Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title | Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title_full | Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title_fullStr | Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title_full_unstemmed | Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title_short | Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia |
title_sort | protein kinase c iota regulates pancreatic acinar-to-ductal metaplasia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281025/ https://www.ncbi.nlm.nih.gov/pubmed/22359542 http://dx.doi.org/10.1371/journal.pone.0030509 |
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