Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia

• DOI: 10.1038/srep29133
• Publication Date: 2016-07-01T11:18:33Z
• Authors: Kazumi Ebine; Christina R. Chow; Brian T. DeCant; Holly Z. Hattaway; Paul J. Grippo; Krishan Kumar; Hidayatullah G. M...
• Keywords: 0301 basic medicine; Metaplasia; Epithelial-Mesenchymal Transition; Pancreatic Ducts; Mice, Transgenic; Acinar Cells; Article; 3. Good health; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Disease Models, Animal; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Pancreatitis, Chronic; Animals; Humans; Snail Family Transcription Factors; Signal Transduction

AbstractCells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated. Surprisingly, Slug attenuated Kras-induced ADM development, ERK1/2 phosphorylation and proliferation. Co-expression of Slug with Kras also attenuated chronic pancreatitis-induced changes in ADM development and fibrosis. In addition, Slug attenuated TGF-α-induced acinar cell metaplasia to ductal structures and TGF-α-induced expression of ductal markers inex vivoacinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in theex vivocultures induced expression of ductal markers and reversed the effects of Slug by inducing ductal structures. In addition, blocking ROCK1/2 activity in Slug-expressing Kras mice reversed the inhibitory effects of Slug on ADM, ERK1/2 phosphorylation, proliferation and fibrosis. Overall, these results increase our understanding of the role of Slug in ADM, an early event that can eventually lead to pancreatic cancer development.