Journal
BRITISH JOURNAL OF CANCER
Volume 104, Issue 6, Pages 1038-1048Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.31
Keywords
activated Kras; invasion; metastasis; motility; pancreatic cancer
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Funding
- National Institutes of Health [CA RO1 CA78590, UO1 CA111294, RO1 CA133774, RO1 CA131944, P50 CA 127297]
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BACKGROUND: Pancreatic cancer (PC) harbours an activated point mutation (Kras(G12D)) in the Kras proto-oncogene that has been demonstrated to promote the development of PC. METHODS: This study was designed to investigate the effect of the oncogenic Kras(G12D) allele on aggressiveness and metastatic potential of PC cells. We silenced the oncogenic Kras(G12D) allele expression in CD18/HPAF and ASPC1 cell lines by stable expression of shRNA specific to the Kras(G12D) allele. RESULTS: The Kras(G12D) knockdown cells exhibited a significant decrease in motility (P<0.0001), invasion (P<0.0001), anchorage-dependent (P<0.0001) and anchorage-independent growth (P<0.0001), proliferation (Po0.005) and an increase in cell doubling time (Po0.005) in vitro and a decrease in the incidence of metastases upon orthotopic implantation into nude mice. The knockdown of the Kras(G12D) allele led to a significant increase in the expression of E-cadherin (mRNA and protein) both in vitro and in vivo. This was associated with a decrease in the expression of phoshpo-ERK-1/2, NF-kappa B and MMP-9, and transcription factors such as delta EF1, Snail and ETV4. Furthermore, the expression of several proteins involved in cell survival, invasion and metastasis was decreased in the Kras(G12D) knockdown cells. CONCLUSIONS: The results of this study suggest that the Kras(G12D) allele promotes metastasis in PC cells partly through the downregulation of E-cadherin. British Journal of Cancer (2011) 104, 1038-1048. doi: 10.1038/bjc.2011.31 www.bjcancer.com
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