國家衛生研究院 NHRI:Item 3990099045/3062
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    题名: Effect of connective tissue growth factor on hypoxia-inducible factor 1 alpha degradation and tumour angiogenesis
    作者: Chang, CC;Lin, MT;Lin, BR;Jeng, YM;Chen, ST;Chu, CY;Chen, RJ;Chang, KJ;Yang, PC;Kuo, ML
    贡献者: National Institute of Cancer Research
    摘要: Background: Connective tissue growth factor (CTGF) inhibits the metastatic activity of human lung cancer cells in a mouse model; however, the mechanism of this modulation is unclear. We investigated the role of angiogenesis in this process. Methods: CL1-5 and A549 human lung adenocarcinoma cells were stably transfected with vectors containing CTGF or hypoxia-inducible factor (HIF) la or with vector controls. Transfected cells were injected into nude mice (n = 10 per group), and tumor growth, metastasis, and mouse survival were measured. Excised xenograft tumors and primary human lung adenocarcinomas (n = 24) were subjected to immunohistochemistry with antibodies to the endothelial cell marker CD31 and to CTGF. Expression of HIF-1 alpha and vascular endothelial growth factor (VEGF) A was assessed in vitro by using reporter gene assays. Cells were transiently transfected with HIF-1 alpha mutant and antisense arrest-defective 1 protein (ARD-1), and HIF-1 alpha acetylation was assayed by immunoprecipitation. All statistical tests were two-sided. Results: Xenograft tumors derived from CTGF transfectants grew more slowly than those from control-transfected cells and had reduced expression of HIF-1a and VEGF-A, vascularization (as assessed by CD31 expression), and metastasis (all P <.001). Xenograft tumors derived from CTGF-overexpressing cells that were transfected with HIF-1 alpha had higher VEGF-A expression than CTGF-overexpressing xenografts. Mice with CTGF/HIF-1 alpha xenografts had lower survival than mice carrying CTGF-overexpressing xenografts (CL1-5/Neo, mean = 69.6 days, 95% confidence interval [CI] -53.9 to 85.3 days versus CL1-5/CTGF, mean = 102.1 days, 95% CI = 92.1 to 112.1 days; P =.001, CL1-5/CTGF, mean = 102.1 days, 95% CI = 92.1 to 112.1 days versus CL1-5/CTGF/HIF-1 alpha, mean = 81.7 days, 95% CI = 66.5 to 96.9 days; P =.011, CL1-5/Neo, mean = 69.6 days, 95% CI = 53.9 to 85.3 days versus CL1-5/CTGF/HIF-1 alpha, mean =81.7 days, 95% CI = 66.5 to 96.9 days; P =.122). Tumors of patients with the same disease stage but with high CTGF protein expression had reduced microvessel density compared with tumors with low expression. Transfection with antisense-ARDI decreased the level of acetylated HIF-1 alpha and restored HIF-1 alpha and VEGF-A expression in CTGF-overexpressing cells. Conclusion: CTGF inhibition of metastasis involves the inhibition of VEGF-A-dependent angiogenesis, possibly by promoting HIF-1 alpha protein degradation.
    关键词: Oncology
    日期: 2006-07-19
    關聯: Journal of the National Cancer Institute. 2006 Jul;98(14):984-995.
    Link to: http://dx.doi.org/10.1093/jnci/djj242
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0027-8874&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000239279000012
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33746776975
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