| First Author | Ding L | Year | 2017 |
| Journal | J Pathol | Volume | 243 |
| Issue | 1 | Pages | 65-77 |
| PubMed ID | 28639695 | Mgi Jnum | J:246658 |
| Mgi Id | MGI:5916589 | Doi | 10.1002/path.4928 |
| Citation | Ding L, et al. (2017) Glycogen synthase kinase-3beta ablation limits pancreatitis-induced acinar-to-ductal metaplasia. J Pathol 243(1):65-77 |
| abstractText | Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3beta) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3beta promotes TGF-alpha-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3beta attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3beta ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3beta regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3beta participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
