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SHR Neuro Cancer Cardio Lipid Metab Microb

Zanini, S; Giovinazzo, F; Alaimo, D; Lawrence, B; Pfragner, R; Bassi, C; Modlin, I; Kidd, M.
GNA15 expression in small intestinal neuroendocrine neoplasia: functional and signalling pathway analyses.
Cell Signal. 2015; 27(5):899-907 Doi: 10.1016/j.cellsig.2015.02.001
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Co-authors Med Uni Graz: Pfragner Roswitha
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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. Copyright © 2015 Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing): Cell Line, Tumor -; Cells, Cultured -; GTP-Binding Protein alpha Subunits, Gq-G11 - analysis; GTP-Binding Protein alpha Subunits, Gq-G11 - genetics; Gastric Mucosa - metabolism; Gene Expression Regulation, Neoplastic -; Humans -; Intestinal Neoplasms - genetics; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestine, Small - metabolism; Intestine, Small - pathology; MAP Kinase Signaling System -; NF-kappa B - metabolism; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Pancreas - metabolism; Pancreas - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction -; Stomach - pathology; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology
Find related publications in this database (Keywords): GNA15; G alpha 15; Small intestinal neuroendocrine neoplasia; G protein; KRJ-I cell line; beta(1) adrenergic receptor