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The neuromedin B receptor (NMB-R), a member of the mammalian bombesin receptor family, is frequently overexpressed in various tumors. In the present study, we found that exposure to hypoxic conditions increases the levels of  NMBR  mRNA and protein in breast cancer cells, which are tightly regulated by hypoxia-inducible factor-1α (HIF-1α). We confirmed the effect of HIF-1α on  NMBR  transcription by performing an  NMBR  promoter-driven reporter assay and then identified a functional hypoxia-responsive element (HRE) in the human  NMBR  promoter region. Further, the binding of HIF-1α to the  NMBR  promoter was corroborated by electrophoretic mobility shift and chromatin immunoprecipitation assays, which showed that HIF-1α specifically and directly bound to the  NMBR  promoter in response to hypoxia. Immunohistochemical analysis of a xenograft and a human breast cancer tissue array revealed a significant correlation between NMB-R and HIF-1α expression. Taken together, our findings indicate that hypoxia induces NMB-R expression through a novel mechanism to regulate HIF-1α expression in breast cancer cells.

Hypoxia Regulates the Expression of the Neuromedin B Receptor through a Mechanism Dependent on Hypoxia-Inducible Factor-1α