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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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-94150-3 |
| _version_ | 1818851923912032256 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T07:12:45Z |
| format | Article |
| id | doaj.art-93784b7c519a4fadb855ff83a5d6b591 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T07:12:45Z |
| publishDate | 2021-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-93784b7c519a4fadb855ff83a5d6b5912022-12-21T20:31:09ZengNature PortfolioScientific Reports2045-23222021-07-0111111010.1038/s41598-021-94150-3Gα15 in early onset of pancreatic ductal adenocarcinomaGiulio Innamorati0Thomas M. Wilkie1Giorgio Malpeli2Salvatore Paiella3Silvia Grasso4Borislav Rusev5Biagio Eugenio Leone6Maria Teresa Valenti7Luca dalle Carbonare8Samuele Cheri9Alice Giacomazzi10Marco Zanotto11Vanessa Guardini12Michela Deiana13Donato Zipeto14Michela Serena15Marco Parenti16Francesca Guzzi17Rita Teresa Lawlor18Giovanni Malerba19Antonio Mori20Giuseppe Malleo21Luca Giacomello22Roberto Salvia23Claudio Bassi24Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaPharmacology Department, UT Southwestern Medical CenterDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaARC-Net Research Centre, University and Hospital Trust of VeronaDepartment of Medicine and Surgery, University of Milano-BicoccaDepartment of Medicine, University of VeronaDepartment of Medicine, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Medicine and Surgery, University of Milano-BicoccaDepartment of Medicine and Surgery, University of Milano-BicoccaARC-Net Research Centre, University and Hospital Trust of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of VeronaAbstract 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.https://doi.org/10.1038/s41598-021-94150-3 |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | Gα15 in early onset of pancreatic ductal adenocarcinoma |
| title_sort | gα15 in early onset of pancreatic ductal adenocarcinoma |
| url | https://doi.org/10.1038/s41598-021-94150-3 |
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