Time filter

Source Type

Lee N.O.,Liver and Pancreatobiliary Cancer Research Branch | Park J.-W.,Liver and Pancreatobiliary Cancer Research Branch | Park J.-W.,Center for Liver Cancer | Lee J.A.,Liver and Pancreatobiliary Cancer Research Branch | And 4 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose 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 diVerent cascades in the VEGF pathway respond to COX-2 inhibition, depending on the cell types. Methods 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. Results 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. Conclusion These Wndings disclose a novel cell-dependent regulatory mechanism of VEGF involving DDR2 gene in HCC cells. © 2011 Springer-Verlag.


Park J.-W.,Liver and Pancreatobiliary Cancer Research Branch | Park J.-W.,Center for Liver Cancer | Lee Y.-S.,National Cancer Center | Kim J.S.,Liver and Pancreatobiliary Cancer Research Branch | And 8 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2015

Purpose: Discoidin domain receptors (DDRs) have been identified as tyrosine kinase receptors for collagen, and the overexpression of DDR1 was correlated with hepatocellular carcinoma (HCC) progression in vitro. Little is known about DDR2 on HCC cells, and we investigated the expression and function of DDR2 in human HCC cells. Methods: Expression of DDR2 in human HCC cell lines and patient HCC tissues was observed. The suppression of DDR2 by siRNA against DDR2 was performed in vitro and in vivo study. Results: All of HCC cell lines expressed DDR2 mRNA, and all HCC tissues from the ten patients with HCC demonstrated DDR2 mRNA expression. Transfection of DDR2 siRNA significantly inhibits cell growth compared to cells with nontarget siRNA transfection in vitro (P < 0.001). In SNU182, Hep3B, and HeLa cell xenograft models, there was a significant difference in average tumor volumes after 12 days of the DDR2 siRNA injection (P < 0.05) in SNU182 xenograft mice. DDR2 siRNA injection decreased the mean tumor volume by 65.6 % compared to that of the control. The apoptosis analysis demonstrated that DDR2 siRNA treatment significantly increased apoptotic cells (P < 0.01). Cell migration (P < 0.05) and cell invasion (P < 0.01) were significantly decreased by DDR2 siRNA treatment. Conclusions: The inhibition of DDR2 by RNA interference suppressed in vivo and in vitro growth of human HCC cells. Our results may support that the use of DDR2 as a novel target of HCC treatment through control of tumor apoptosis, migration, and invasion. © 2015, Springer-Verlag Berlin Heidelberg.


PubMed | Liver and Pancreatobiliary Cancer Research Branch
Type: Journal Article | Journal: Journal of cancer research and clinical oncology | Year: 2012

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-1 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.


PubMed | Liver and Pancreatobiliary Cancer Research Branch, Center for Liver Cancer and National Cancer Center
Type: Journal Article | Journal: Journal of cancer research and clinical oncology | Year: 2015

Discoidin domain receptors (DDRs) have been identified as tyrosine kinase receptors for collagen, and the overexpression of DDR1 was correlated with hepatocellular carcinoma (HCC) progression in vitro. Little is known about DDR2 on HCC cells, and we investigated the expression and function of DDR2 in human HCC cells.Expression of DDR2 in human HCC cell lines and patient HCC tissues was observed. The suppression of DDR2 by siRNA against DDR2 was performed in vitro and in vivo study.All of HCC cell lines expressed DDR2 mRNA, and all HCC tissues from the ten patients with HCC demonstrated DDR2 mRNA expression. Transfection of DDR2 siRNA significantly inhibits cell growth compared to cells with nontarget siRNA transfection in vitro (P<0.001). In SNU182, Hep3B, and HeLa cell xenograft models, there was a significant difference in average tumor volumes after 12days of the DDR2 siRNA injection (P<0.05) in SNU182 xenograft mice. DDR2 siRNA injection decreased the mean tumor volume by 65.6% compared to that of the control. The apoptosis analysis demonstrated that DDR2 siRNA treatment significantly increased apoptotic cells (P<0.01). Cell migration (P<0.05) and cell invasion (P<0.01) were significantly decreased by DDR2 siRNA treatment.The inhibition of DDR2 by RNA interference suppressed in vivo and in vitro growth of human HCC cells. Our results may support that the use of DDR2 as a novel target of HCC treatment through control of tumor apoptosis, migration, and invasion.

Loading Liver and Pancreatobiliary Cancer Research Branch collaborators
Loading Liver and Pancreatobiliary Cancer Research Branch collaborators