Cyclooxygenase-2 pathway correlates with vascular endothelial growth factor expression and tumor angiogenesis in hepatitis B virus-associated hepatocellular carcinoma

被引:19
作者
Cheng, ASL [1 ]
Chan, HLY
To, KAF
Leung, WK
Chan, KK
Liew, CT
Sung, JJY
机构
[1] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Sha Tin, Hong Kong, Peoples R China
[2] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Sha Tin, Hong Kong, Peoples R China
关键词
cyclooxygenase-2; vascular endothelial growth factor; angiogenesis; hepatitis B virus; hepatocellular carcinoma;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Evidence indicates that cyclooxygenase (COX)-2-derived prostaglandins (PGs) contribute to tumor growth by inducing angiogenesis. We investigated the role of COX-2 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). COX-2 and vascular endothelial growth factor (VEGF) expressions were examined by immunohistochemistry in 24 HBV-associated HCC. Tumor micro-vessel density (MVD) was assessed using CD34 immunohistochemistry. Hep3B HCC cell line, which carries integrated HBV genome, was stably transfected with human COX-2 cDNA. COX-2 and VEGF expressions were determined by Western blot while PG level was determined by ELISA. The effects of PGs on VEGF expression were also investigated. Expression of COX-2 and VEGF in HCC cells were observed in 19 (79%) and 16 (67%) cases, respectively. Well-differentiated HCC expressed COX-2 more strongly than less-differentiated HCC (p<0.001). COX-2 expression was found to correlate with VEGF expression and MVD (p=0.003 and 0.004, respectively). COX-2 overexpressing Hep3B clone had higher VEGF expression as compared to non-COX-2 expressing clone and parental cells. Treatment of the COX-2 overexpressing cells with a COX-2-selective inhibitor, NS-398 (10 muM), decreased PGE(2) level and attenuated VEGF expression. Addition of PGE(2) (10 muM) and the stable analog of PGI(2), carbaprostacyclin (5 muM), to Hep3B cells also increased VEGF expression. Upregulation of COX-2 correlates with VEGF expression and tumor angiogenesis in HBV-associated HCC. Moreover, COX-2 up-regulates VEGF expression in HCC cells, possibly via PGs production. Selective inhibition of COX-2 may block HCC associated angiogenesis and thus provides a rational approach for treatment of this malignancy.
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页码:853 / 860
页数:8
相关论文
共 46 条
[31]  
Sales KJ, 2002, CANCER RES, V62, P424
[32]  
SANO H, 1995, CANCER RES, V55, P3785
[33]  
Schmedtje JF, 1997, J BIOL CHEM, V272, P601
[34]   The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis [J].
Steinbach, G ;
Lynch, PM ;
Phillips, RKS ;
Wallace, MH ;
Hawk, E ;
Gordon, GB ;
Wakabayashi, N ;
Saunders, B ;
Shen, Y ;
Fujimura, T ;
Su, LK ;
Levin, B ;
Godio, L ;
Patterson, S ;
Rodriguez-Bigas, MA ;
Jester, SL ;
King, KL ;
Schumacher, M ;
Abbruzzese, J ;
DuBois, RN ;
Hittelman, WN ;
Zimmerman, S ;
Sherman, JW ;
Kelloff, G .
NEW ENGLAND JOURNAL OF MEDICINE, 2000, 342 (26) :1946-1952
[35]   The mechanisms of angiogenesis in hepatocellular carcinoma: Angiogenic switch during tumor progression [J].
Sugimachi, K ;
Tanaka, S ;
Terashi, T ;
Taguchi, K ;
Rikimaru, T ;
Sugimachi, K .
SURGERY, 2002, 131 (01) :S135-S141
[36]   DETECTION OF INTEGRATED HEPATITIS-B VIRUS-DNA IN HEPATOCELLULAR-CARCINOMA CELL-LINES BY NONRADIOACTIVE INSITU HYBRIDIZATION [J].
TAY, N ;
CHAN, SH ;
REN, EC .
JOURNAL OF MEDICAL VIROLOGY, 1990, 30 (04) :266-271
[37]   Evidences for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines [J].
Tsuji, S ;
Kawano, S ;
Sawaoka, H ;
Takei, Y ;
Kobayashi, I ;
Nagano, K ;
Fusamoto, H ;
Kamada, T .
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 1996, 55 (03) :179-183
[38]   Cyclooxygenase regulates angiogenesis induced by colon cancer cells [J].
Tsujii, M ;
Kawano, S ;
Tsuji, S ;
Sawaoka, H ;
Hori, M ;
DuBois, RN .
CELL, 1998, 93 (05) :705-716
[39]  
Uefuji K, 1998, J SURG ONCOL, V69, P168, DOI 10.1002/(SICI)1096-9098(199811)69:3<168::AID-JSO9>3.0.CO
[40]  
2-0