title: GNA15 expression in small intestinal neuroendocrine neoplasia: functional and signalling pathway analyses.
abstract: Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) comprises a heterogeneous group of tumours that exhibit widely divergent biological behaviour. The identification of new targetable GPCR-pathways involved in regulating cell function could help to identify new therapeutic strategies. We assessed the function of a haematopoietic stem cell heterotrimeric G-protein, Gα15, in gut neuroendocrine cell models and examined the clinical implications of its over expression. Functional assays were undertaken to define the role of GNA15 in the small intestinal NEN cell line KRJ-I and in clinical samples from small intestinal NENs using quantitative polymerase chain reaction, western blot, proliferation and apoptosis assays, immunoprecipitation, immunohistochemistry (IHC) and automated quantitative analysis (AQUA). GNA15 was not expressed in normal neuroendocrine cells but was overexpressed in GEP-NEN cell lines. In KRJ-I cells, decreased expression of GNA15 was associated with inhibition of proliferation, activation of apoptosis and differential effects on pro-proliferative ERK, NFκB and Akt pathway signalling. Moreover, Gα15 was demonstrated to couple to the ß1 adrenergic receptor and modulated proliferative signals through this GPCR. Transcript and protein levels of GNA15 were significantly elevated in primary and metastatic tumours compared to normal mucosa and were particularly increased in low Ki-67 expressing tumours. IHC and AQUA revealed that a higher Gα15 expression was associated with a poorer survival. GNA15 may have a pathobiological role in SI-NENs. Targeting this signalling mediator could provide an opportunity for the development of new therapeutic strategies for this tumour type.
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA; Department of Surgery, Laboratory of Translational Surgery, LURM, Hospital of G.B. Rossi, University of Verona, Piazzale L.A. Scuro, IT-37134 Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Zanini
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA; Department of Surgery, Laboratory of Translational Surgery, LURM, Hospital of G.B. Rossi, University of Verona, Piazzale L.A. Scuro, IT-37134 Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giovinazzo
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Alaimo
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Lawrence
authors.affiliation: Institute of Pathophysiology and Immunology, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Pfragner
authors.affiliation: Department of Surgery, Laboratory of Translational Surgery, LURM, Hospital of G.B. Rossi, University of Verona, Piazzale L.A. Scuro, IT-37134 Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
authors.forename: Irvin
authors.initials: I
authors.lastname: Modlin
authors.affiliation: Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT 06520-8062, USA. Electronic address: mark.kidd@yale.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000032:analysis / Q000235:genetics*; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: G protein; GNA15; Gα15; KRJ-I cell line; Small intestinal neuroendocrine neoplasia; ß(1) adrenergic receptor