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© The Author 2006. Published by Oxford University Press.
ARTICLE |
Effect of Connective Tissue Growth Factor on Hypoxia-Inducible Factor 1
Degradation and Tumor Angiogenesis
Affiliations of authors: Angiogenesis Research Center, Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan (CCC, MLK); Departments of Surgery (MTL, BRL, KJC), Pathology (YMJ), Pediatrics (STC), and Dermatology (CYC), National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan (RJC); Department of Internal Medicine, National Taiwan University Hospital, National Health Research Institutes, and Institute of Biomedical Sciences, Taipei, Taiwan (PCY).
Correspondence to: Min-Liang Kuo, PhD, Angiogenesis Research Center, Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1 Sec. 1 Jen-Ai Rd., Taipei 100, Taiwan (e-mail: toxkml{at}ha.mc.ntu.edu.tw).
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) 1
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 and vascular endothelial growth factor (VEGF) A was assessed in vitro by using reporter gene assays. Cells were transiently transfected with HIF-1 mutant and antisense arrest-defective 1 protein (ARD-1), and HIF-1 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-1 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 had higher VEGF-A expression than CTGF-overexpressing xenografts. Mice with CTGF/HIF-1 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, 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, 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-ARD1 decreased the level of acetylated HIF-1 and restored HIF-1 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 protein degradation.
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Choking Hypoxia-Inducible Factor 1: A Novel Mechanism for Connective Tissue Growth Factor Inhibition of Angiogenesis
- Francesca Tosetti, Douglas M. Noonan, and Adriana Albini
J Natl Cancer Inst 2006 98: 946-948.[Extract] [Full Text] [PDF]
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