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http://ir.nhri.org.tw/handle/3990099045/3062
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| Title: | Effect of connective tissue growth factor on hypoxia-inducible factor 1 alpha degradation and tumour angiogenesis |
| Authors: | Chang, CC;Lin, MT;Lin, BR;Jeng, YM;Chen, ST;Chu, CY;Chen, RJ;Chang, KJ;Yang, PC;Kuo, ML |
| Contributors: | National Institute of Cancer Research |
| Abstract: | 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. |
| Keywords: | Oncology |
| Date: | 2006-07-19 |
| Relation: | 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 |
| Appears in Collections: | [其他] 期刊論文
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| 000239279000012.pdf | | 917Kb | Adobe PDF | 635 | View/Open |
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