Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia.
Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia.
复制标题
SLUG通过阻止KRAS诱导的腺泡导管化生症来抑制胰腺癌的开始。
DOI：
10.1038/srep29133
复制
发表时间：
2016-07-01
影响因子：
4.6
通讯作者：
Munshi HG
中科院分区：
文献类型：
--
作者：
Ebine K;Chow CR;DeCant BT;Hattaway HZ;Grippo PJ;Kumar K;Munshi HG
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.
