<i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma
For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (<i>ASS1</i>, <i>EIF4G1</i>, <i&...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/14/4856 |
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| author | Irene Dell’Anno Marcella Barbarino Elisa Barone Antonio Giordano Luca Luzzi Maria Bottaro Loredana Migliore Silvia Agostini Alessandra Melani Ombretta Melaiu Calogerina Catalano Monica Cipollini Roberto Silvestri Alda Corrado Federica Gemignani Stefano Landi |
| author_facet | Irene Dell’Anno Marcella Barbarino Elisa Barone Antonio Giordano Luca Luzzi Maria Bottaro Loredana Migliore Silvia Agostini Alessandra Melani Ombretta Melaiu Calogerina Catalano Monica Cipollini Roberto Silvestri Alda Corrado Federica Gemignani Stefano Landi |
| author_sort | Irene Dell’Anno |
| collection | DOAJ |
| description | For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (<i>ASS1</i>, <i>EIF4G1</i>, <i>GALNT7</i>, <i>GLUT1</i>, <i>IGF2BP3</i> (<i>IMP3</i>), <i>ITGA4</i>, <i>RAN</i>, <i>SOD1</i>, and <i>THBS2</i>) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression (“passenger genes”). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of <i>EIF4G1</i> and <i>RAN</i> significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following <i>RAN</i> gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As <i>EIF4G1</i> and <i>RAN</i> deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine. |
| first_indexed | 2024-03-10T18:35:20Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:35:20Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2d29070c916e4f4084c7c9a969844b5d2023-11-20T06:16:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-012114485610.3390/ijms21144856<i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural MesotheliomaIrene Dell’Anno0Marcella Barbarino1Elisa Barone2Antonio Giordano3Luca Luzzi4Maria Bottaro5Loredana Migliore6Silvia Agostini7Alessandra Melani8Ombretta Melaiu9Calogerina Catalano10Monica Cipollini11Roberto Silvestri12Alda Corrado13Federica Gemignani14Stefano Landi15Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Medicine, Surgery and Neurosciences, Siena University Hospital, 53100 Siena, ItalyDepartment of Medical Biotechnologies, University of Siena, 53100 Siena, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyDepartment of Biology, Genetic Unit, University of Pisa, 56126 Pisa, ItalyFor malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (<i>ASS1</i>, <i>EIF4G1</i>, <i>GALNT7</i>, <i>GLUT1</i>, <i>IGF2BP3</i> (<i>IMP3</i>), <i>ITGA4</i>, <i>RAN</i>, <i>SOD1</i>, and <i>THBS2</i>) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression (“passenger genes”). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of <i>EIF4G1</i> and <i>RAN</i> significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following <i>RAN</i> gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As <i>EIF4G1</i> and <i>RAN</i> deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.https://www.mdpi.com/1422-0067/21/14/4856cancer driving geneEIF4G1MPMRANsiRNAimportazole |
| spellingShingle | Irene Dell’Anno Marcella Barbarino Elisa Barone Antonio Giordano Luca Luzzi Maria Bottaro Loredana Migliore Silvia Agostini Alessandra Melani Ombretta Melaiu Calogerina Catalano Monica Cipollini Roberto Silvestri Alda Corrado Federica Gemignani Stefano Landi <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma International Journal of Molecular Sciences cancer driving gene EIF4G1 MPM RAN siRNA importazole |
| title | <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma |
| title_full | <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma |
| title_fullStr | <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma |
| title_full_unstemmed | <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma |
| title_short | <i>EIF4G1</i> and <i>RAN</i> as Possible Drivers for Malignant Pleural Mesothelioma |
| title_sort | i eif4g1 i and i ran i as possible drivers for malignant pleural mesothelioma |
| topic | cancer driving gene EIF4G1 MPM RAN siRNA importazole |
| url | https://www.mdpi.com/1422-0067/21/14/4856 |
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