Gα15 in early onset of pancreatic ductal adenocarcinoma

Abstract The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreati...

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Autores principales:	Giulio Innamorati, Thomas M. Wilkie, Giorgio Malpeli, Salvatore Paiella, Silvia Grasso, Borislav Rusev, Biagio Eugenio Leone, Maria Teresa Valenti, Luca dalle Carbonare, Samuele Cheri, Alice Giacomazzi, Marco Zanotto, Vanessa Guardini, Michela Deiana, Donato Zipeto, Michela Serena, Marco Parenti, Francesca Guzzi, Rita Teresa Lawlor, Giovanni Malerba, Antonio Mori, Giuseppe Malleo, Luca Giacomello, Roberto Salvia, Claudio Bassi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/93784b7c519a4fadb855ff83a5d6b591
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spelling	oai:doaj.org-article:93784b7c519a4fadb855ff83a5d6b5912021-12-02T16:50:23ZGα15 in early onset of pancreatic ductal adenocarcinoma10.1038/s41598-021-94150-32045-2322https://doaj.org/article/93784b7c519a4fadb855ff83a5d6b5912021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94150-3https://doaj.org/toc/2045-2322Abstract The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for G NA 15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.Giulio InnamoratiThomas M. WilkieGiorgio MalpeliSalvatore PaiellaSilvia GrassoBorislav RusevBiagio Eugenio LeoneMaria Teresa ValentiLuca dalle CarbonareSamuele CheriAlice GiacomazziMarco ZanottoVanessa GuardiniMichela DeianaDonato ZipetoMichela SerenaMarco ParentiFrancesca GuzziRita Teresa LawlorGiovanni MalerbaAntonio MoriGiuseppe MalleoLuca GiacomelloRoberto SalviaClaudio BassiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giulio Innamorati Thomas M. Wilkie Giorgio Malpeli Salvatore Paiella Silvia Grasso Borislav Rusev Biagio Eugenio Leone Maria Teresa Valenti Luca dalle Carbonare Samuele Cheri Alice Giacomazzi Marco Zanotto Vanessa Guardini Michela Deiana Donato Zipeto Michela Serena Marco Parenti Francesca Guzzi Rita Teresa Lawlor Giovanni Malerba Antonio Mori Giuseppe Malleo Luca Giacomello Roberto Salvia Claudio Bassi Gα15 in early onset of pancreatic ductal adenocarcinoma
description	Abstract The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for G NA 15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.
format	article
author	Giulio Innamorati Thomas M. Wilkie Giorgio Malpeli Salvatore Paiella Silvia Grasso Borislav Rusev Biagio Eugenio Leone Maria Teresa Valenti Luca dalle Carbonare Samuele Cheri Alice Giacomazzi Marco Zanotto Vanessa Guardini Michela Deiana Donato Zipeto Michela Serena Marco Parenti Francesca Guzzi Rita Teresa Lawlor Giovanni Malerba Antonio Mori Giuseppe Malleo Luca Giacomello Roberto Salvia Claudio Bassi
author_facet	Giulio Innamorati Thomas M. Wilkie Giorgio Malpeli Salvatore Paiella Silvia Grasso Borislav Rusev Biagio Eugenio Leone Maria Teresa Valenti Luca dalle Carbonare Samuele Cheri Alice Giacomazzi Marco Zanotto Vanessa Guardini Michela Deiana Donato Zipeto Michela Serena Marco Parenti Francesca Guzzi Rita Teresa Lawlor Giovanni Malerba Antonio Mori Giuseppe Malleo Luca Giacomello Roberto Salvia Claudio Bassi
author_sort	Giulio Innamorati
title	Gα15 in early onset of pancreatic ductal adenocarcinoma
title_short	Gα15 in early onset of pancreatic ductal adenocarcinoma
title_full	Gα15 in early onset of pancreatic ductal adenocarcinoma
title_fullStr	Gα15 in early onset of pancreatic ductal adenocarcinoma
title_full_unstemmed	Gα15 in early onset of pancreatic ductal adenocarcinoma
title_sort	gα15 in early onset of pancreatic ductal adenocarcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/93784b7c519a4fadb855ff83a5d6b591
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Gα15 in early onset of pancreatic ductal adenocarcinoma

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