Journal
SCIENTIFIC REPORTS
Volume 4, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep06538
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Funding
- National Natural Science Foundation of China [81101496, 81172003]
- Research Fund for the Doctoral Program of Higher Education of China [20113234120009]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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Prostaglandin E-2 (PGE(2)) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased beta 1-integrin expression and cell migration; however, the mechanism remains unclear. PGE(2) exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1-4). The present study investigated the effect of EP1 receptor activation on beta 1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE(2) (EP1 agonist), which was suppressed by pretreatment with a beta 1-integrin polyclonal antibody. PGE(2) increased beta 1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE(2) mimicked the effect of PGE(2) treatment. EP1 siRNA blocked PGE(2)-mediated beta 1-integrin expression. 17-PT-PGE(2) treatment induced PKC and NF-kappa B activation; PKC and NF-kappa B inhibitors suppressed 17-PT-PGE(2)-mediated beta 1-integrin expression. FoxC2, a beta 1-integrin transcription factor, was also upregulated by 17-PT-PGE(2). NF-kappa B inhibitor suppressed 17-PT-PGE(2)-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and beta 1-integrin were all highly expressed in the HCC cases. This study suggested that PGE(2) upregulates beta 1-integrin expression and cell migration in HCC cells by activating the PKC/NF-kappa B signaling pathway. Targeting PGE(2)/EP1/PKC/NF-kappa B/FoxC2/beta 1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.
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