Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis.
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) 1alpha 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-1alpha and vascular endothelial growth factor (VEGF) A was assessed in vitro by using reporter gene assays. Cells were transiently transfected with HIF-1alpha mutant and antisense arrest-defective 1 protein ( ARD-1), and HIF-1alpha 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-1alpha 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-1alpha had higher VEGF-A expression than CTGF-overexpressing xenografts. Mice with CTGF/HIF-1alpha 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-1alpha, 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-1alpha, 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-1alpha and restored HIF-1alpha 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-1alpha protein degradation.[1]References
- Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis. Chang, C.C., Lin, M.T., Lin, B.R., Jeng, Y.M., Chen, S.T., Chu, C.Y., Chen, R.J., Chang, K.J., Yang, P.C., Kuo, M.L. J. Natl. Cancer Inst. (2006) [Pubmed]
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