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Nuclear Factor-B Mediates Angiogenesis and Metastasis of Human Bladder Cancer through the Regulation of Interleukin-8¹

Departments of Cancer Biology [T. K., S. H., S. J. K., M. B-E., D. J. M., C. P. N. D.] and Urology [P. S., A. K., C. P. N. D.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: Interleukin (IL)-8 is an important mediator of angiogenesis, tumorigenicity, and metastasis in transitional cell carcinoma (TCC) of the bladder. Nuclear factor B (NF-B)/relA regulates IL-8 expression in several neoplasms. The purpose of this study was to determine whether the organ microenvironment (hypoxia, acidosis) regulates the expression of IL-8 in TCC via NF-B, and whether inhibition of NF-B function by mutant IB- prevents induction of IL-8 expression.

Experimental Design: IL-8 mRNA expression and protein production by human TCC cell lines (UM-UC-14, HTB-9, RT-4, KU-7 and 253J B-V) were measured by Northern blot analysis and ELISA under acidic (pH 7.35–6.0) and hypoxic (1.0% O₂) conditions. The involvement of NF-B and activator protein 1 in the regulation of IL-8 production was evaluated by electrophoretic mobility shift assay. Furthermore, the tumorigenicity and metastatic potential of UM-UC-14 cells were determined after transfection with mutant IB-.

Results: We found that acidic and hypoxic conditions increased IL-8 mRNA expression and protein production by several, but not all, TCC cell lines evaluated. NF-B, but not activator protein 1, was inducibly activated in UM-UC-14 under both acidic and hypoxic conditions, but not in UM-UC-14 mutant IB- transfectants. Tumor growth and lymph node metastasis were inhibited in UM-UC-14 mutant IB- transfectants compared with UM-UC-14 controls. This effect was associated with the inhibition of IL-8 production, cellular proliferation, and angiogenesis.

Conclusions: These results suggest that TCCs of the bladder have heterogenic responses to physicochemical changes in the microenvironment and identify NF-B as a potential molecular target for therapy.

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