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

Kazumi Ebine, Christina R. Chow, Brian T. Decant, Holly Z. Hattaway, Paul J. Grippo, Krishan Kumar, Hidayatullah G. Munshi*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article number29133
JournalScientific reports
Volume6
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • General

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