title: Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia.
abstract: Cells 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 in ex vivo acinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in the ex vivo cultures 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.
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ebine
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.|The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Chow
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: DeCant
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Holly Z
authors.initials: HZ
authors.lastname: Hattaway
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.|Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.|The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA.|Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D061354:Acinar Cells / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D008679:Metaplasia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000235:genetics*
chemical_list: C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)