Journal
ONCOGENE
Volume 33, Issue 19, Pages 2454-2463Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2013.204
Keywords
pancreatic cancer; PanIN; EVI1; KRAS; microRNA
Funding
- Industrial Technology Research Grant Program from the New Energy and Industrial Technology Development Organization (NEDO) of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Cell Science Research Foundation
- Grants-in-Aid for Scientific Research [26860474] Funding Source: KAKEN
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Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.
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