title: Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis.
abstract: Angiogenesis plays a crucial role in tumor development and growth. The present study was carried out to investigate the potential involvement of the cyclooxygenase-2 (Cox-2) pathway in the regulation of angiogenesis in hepatocellular carcinoma (HCC). We inhibited Cox-2 expression in HCC cell line HuH-7 by selective Cox-2 inhibitor (SC-58635) or Cox-2 siRNA. Conditioned media (CMs) from HuH-7 cells were used in angiogenic assays in vitro and in vivo. Compared with CMs from untreated and negative siRNA treated HuH-7 cells, CMs from SC-58635 and Cox-2 siRNA treated HuH-7 dramatically suppressed the proliferation, migration, and differentiation of human umbilical vein endothelial cells (HUVECs) in vitro and neovascularization in vivo. These inhibitory effects could be partially reversed by the addition of exogenous PGE2 to CMs. Furthermore, Cox-2 inhibition by SC-58635 resulted in PGE2 reduction accompanied by the down-regulation of four PGE2 receptor (EP receptor) subtypes. Treatment with SC-58635 led to the down-expression of proangiogenic factors such as VEGF, HGF, FGF2, ANGPT1 and ANGPT2 in HCC. An approximately 78% reduction of VEGF level has been found in the CM from SC-58635 treated HuH-7. Our results suggest an involvement of Cox-2 in the control of HCC-associated angiogenesis. PGE2 as a vital angiogenic factor may act directly on endothelial cells to promote HuH-7-stimulated angiogenic process. Moreover, Cox-2/PGE2/EP/VEGF pathway possibly also contributes to tumor angiogenesis in HCC. This study provides the rationale for clinical studies of Cox-2 inhibitors on the treatment or chemoprevention of HCC.
authors.affiliation: Department of Hepatobiliary Sugery, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qing-Tao
authors.initials: QT
authors.lastname: Zhao
authors.forename: Shu-Qiang
authors.initials: SQ
authors.lastname: Yue
authors.forename: Zhong
authors.initials: Z
authors.lastname: Cui
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.forename: Hui-Hong
authors.initials: HH
authors.lastname: Zhai
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Zhang
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D017077:Culture Media, Conditioned; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000096:biosynthesis; D004338:Drug Combinations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007797:Laminin; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000517:prevention & control; D011509:Proteoglycans; D034741:RNA, Small Interfering / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D052246:Cyclooxygenase 2 Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen; D051546:Cyclooxygenase 2; D015232:Dinoprostone