Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin

Background:Pancreatic cancer (PC) harbours an activated point mutation (KrasG12D) 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 KrasG12D allele on aggressiveness and metastatic potential of PC cells. We silenced the oncogenic KrasG12D allele expression in CD18/HPAF and ASPC1 cell lines by stable expression of shRNA specific to the KrasG12Dallele.Results:The KrasG12D 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 (P<0.005) and an increase in cell doubling time (P<0.005) in vitro and a decrease in the incidence of metastases upon orthotopic implantation into nude mice. The knockdown of the KrasG12D 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-κB and MMP-9, and transcription factors such as δEF1, Snail and ETV4. Furthermore, the expression of several proteins involved in cell survival, invasion and metastasis was decreased in the KrasG12D knockdown cells.Conclusions:The results of this study suggest that the KrasG12D allele promotes metastasis in PC cells partly through the downregulation of E-cadherin.

• Publication year

  2011

• Venue

  British Journal of Cancer

• Publication date

  2011-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/bjc.2011.31PMID 21364589PMCID 3065271
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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