title: Neuropeptide S receptor 1 (NPSR1) activates cancer-related pathways and is widely expressed in neuroendocrine tumors.
abstract: Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.
authors.affiliation: Pulmonary Division, Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Pulkkinen
authors.forename: S
authors.initials: S
authors.lastname: Ezer
authors.forename: L
authors.initials: L
authors.lastname: Sundman
authors.forename: J
authors.initials: J
authors.lastname: Hagström
authors.forename: S
authors.initials: S
authors.lastname: Remes
authors.forename: C
authors.initials: C
authors.lastname: Söderhäll
authors.forename: D
authors.initials: D
authors.lastname: Greco
authors.forename: G
authors.initials: G
authors.lastname: Dario
authors.forename: C
authors.initials: C
authors.lastname: Haglund
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.forename: J
authors.initials: J
authors.lastname: Arola
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000276:immunology / Q000502:physiology; D049109:Cell Proliferation; D004701:Endocrine Gland Neoplasms / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000473:pathology / Q000503:physiopathology*; D009479:Neuropeptides / Q000276:immunology / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology / Q000502:physiology*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human