title: The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer.
abstract: Using a genome-wide cDNA microarray to search for genes that were specifically up-regulated in non-small cell lung cancers (NSCLC), we identified an abundant expression of neuromedin U (NMU) in the great majority of lung cancers. Immunohistochemical analysis showed a significant association of NMU expression with poorer prognosis of patients with NSCLC. Treatment of NSCLC cells with short interfering RNA against NMU suppressed its expression and inhibited the growth of the cells; on the other hand, the induction of exogenous expression of NMU conferred growth-promoting activity and enhanced cell mobility in vitro. We found that two G protein-coupled receptors, growth hormone secretagogue receptor 1b and neurotensin receptor 1, were also overexpressed in NSCLC cells, and that a heterodimer complex of these receptors functioned as an NMU receptor. The NMU-receptor interaction subsequently induced the generation of a second messenger, cyclic AMP, to activate its downstream genes including transcription factors and cell cycle regulators. Treatment of NSCLC cells with short interfering RNAs for growth hormone secretagogue receptor or neurotensin receptor 1 suppressed the expression of those genes and the growth of NSCLC cells. These data strongly implied that targeting the NMU signaling pathway would be a promising therapeutic strategy for the treatment of lung cancers.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Chiyuki
authors.initials: C
authors.lastname: Furukawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takano
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hayama
authors.forename: Chie
authors.initials: C
authors.lastname: Suzuki
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.forename: Kouki
authors.initials: K
authors.lastname: Inai
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ito
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishimura
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D019281:Dimerization; D004705:Endocytosis; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D054440:Receptors, Ghrelin; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009479:Neuropeptides; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D018028:Receptors, Neurotensin; D011993:Recombinant Fusion Proteins; C114036:neurotensin type 1 receptor; C056900:neuromedin U; C046271:neuromedin U 25; D000242:Cyclic AMP