title: Hypoxia regulates the expression of the neuromedin B receptor through a mechanism dependent on hypoxia-inducible factor-1α.
abstract: 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.
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, South Korea ; Department of Dental Pharmacology, School of Dentistry, Pusan National University, Yangsan, South Korea.
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, South Korea.
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, South Korea ; Department of Dental Pharmacology, School of Dentistry, Pusan National University, Yangsan, South Korea.
authors.forename: Su-Ryun
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, Pusan National University, Yangsan, South Korea.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Bae
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, South Korea.
authors.forename: Moon-Kyoung
authors.initials: MK
authors.lastname: Bae
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018004:Receptors, Bombesin / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D020794:Receptor Protein-Tyrosine Kinases