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Publications (2)5.83 Total impact

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    ABSTRACT: Vascular endothelial growth factor (VEGF) greatly contributes to the progression of hepatocellular carcinoma (HCC). It is reported that a selective cyclooxygenase-2 (COX-2) inhibitor inhibits cellular proliferation and may attenuate VEGF expression in HCC. We propose that different cascades in the VEGF pathway respond to COX-2 inhibition, depending on the cell types. The six human HCC cell lines--Hep3B, SNU387, SNU182, SNU423, SNU449, and PLC/PRF5--were cultured under normoxic and hypoxic conditions. Cells were treated with a selective COX-2 inhibitor (NS-398) and discoidin domain receptor 2 (DDR2) siRNA, and microarray analysis was performed. NS-398 inhibited HCC proliferation and decreased the expression level of VEGF in HCC cells only under normoxia conditions. In hypoxia conditions, VEGF expression level in Hep3B cell was suppressed, while that in SNU387 cell was increased by NS-398 (P < 0.001). The NS-398-induced increase in VEGF expression in SNU387 cell was associated with the up-regulation of the DDR2 gene. NS-398-treated SNU series cells and PLC/PRF5 cells displayed a robust increase in DDR2 mRNA expression. Also, transfection with DDR2 siRNA decreased the VEGF expression level of SNU387, 423, 449 cells under hypoxia conditions (P < 0.05). In vivo chromatin immunoprecipitation assay demonstrated that NS-398 induces the enhancement of HIF-1α binding on VEGF promoter, leading to the increase in VEGF gene expression in hypoxic conditions. There is strong evidence that it is related to the DDR2 gene expression in SNU387 cells. These findings disclose a novel cell-dependent regulatory mechanism of VEGF involving DDR2 gene in HCC cells.
    Journal of Cancer Research and Clinical Oncology 01/2012; 138(1):73-84. · 2.91 Impact Factor
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    ABSTRACT: Expression of cyclooxygenase-2 (COX-2) is involved in the chronic inflammation-related development of hepatocellular carcinoma (HCC), and the use of selective COX-2 inhibitors might provide new chemoprevention strategies for HCC. However, the role of the COX-2 in hepatocarcinogenesis remains obscure, particularly as it has been primarily studied with selective COX-2 inhibitors that may affect other cellular proteins involved in cell proliferation. Therefore, we investigated the effects of the inhibition of COX-2 by the selective COX-2 inhibitor NS-398 as well as by COX-2 specific small interfering RNA (siRNA) in the human HCC cell lines Hep3B and SNU-387. These cell lines expressed COX-2, and NS-398 induced apoptosis of these cells. NS-398 inhibited more than 60% of prostaglandin E(2) (PGE2) production and cell proliferation in a concentration-dependent manner in these cells. The inhibition of proliferation was almost restored with PGE2 supplement, suggesting that NS-398 may inhibit cell growth partially through inhibition of COX-2 and PGE2 production in human HCC cells. However, treatment with NS-398 led to increased expression of COX-2 in Hep3B and SNU-387 cells. To examine the effect of COX-2 depletion on these cells, we electroporated COX-2-specific siRNAs into SNU-387 cells. We observed significant, sequence-specific reductions in COX-2 expression, PGE2 production, and cell proliferation, though the reduction in cell proliferation was less than that induced by NS-398. In conclusion, these data suggest that COX-2 itself is directly involved, though not decisively, in proliferation of human HCC cells. RNA interference may provide a useful tool for manipulating COX-2-related hepatocarcinogenesis in research and therapeutic settings.
    Journal of Cancer Research and Clinical Oncology 04/2006; 132(3):184-92. · 2.91 Impact Factor