Nuclear factor-κB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8

Takashi Karashima, Paul Sweeney, Ashish Kamat, Suyun Huang, Sun J. Kim, Menashe Bar-Eli, David J. McConkey, Colin P.N. Dinney

Research output: Contribution to journalArticle

Abstract

Purpose: Interleukin (IL)-8 is an important mediator of angiogenesis, tumorigenicity, and metastasis in transitional cell carcinoma (TCC) of the bladder. Nuclear factor κB (NF-κB)/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-κB, and whether inhibition of NF-κB function by mutant IκB-α 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-κB 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 IκB-α. 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-κB, 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 IκB-α transfectants. Tumor growth and lymph node metastasis were inhibited in UM-UC-14 mutant IκB-α 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-κB as a potential molecular target for therapy.

Original languageEnglish (US)
Pages (from-to)2786-2797
Number of pages12
JournalClinical Cancer Research
Volume9
Issue number7
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Karashima, T., Sweeney, P., Kamat, A., Huang, S., Kim, S. J., Bar-Eli, M., McConkey, D. J., & Dinney, C. P. N. (2003). Nuclear factor-κB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8. Clinical Cancer Research, 9(7), 2786-2797.