{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:13:05Z","timestamp":1789747985693,"version":"4.0.1"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["Individual Grant nr. 21853"],"award-info":[{"award-number":["Individual Grant nr. 21853"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression (\u201cpassenger genes\u201d). 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 EIF4G1 and RAN 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-\u03b2. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN 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.<\/jats:p>","DOI":"10.3390\/ijms21144856","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T10:45:19Z","timestamp":1594291519000},"page":"4856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["EIF4G1 and RAN as Possible Drivers for Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0782-8823","authenticated-orcid":false,"given":"Irene","family":"Dell\u2019Anno","sequence":"first","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9869-9814","authenticated-orcid":false,"given":"Marcella","family":"Barbarino","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-016X","authenticated-orcid":false,"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Luzzi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neurosciences, Siena University Hospital, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bottaro","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Migliore","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, 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Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Cipollini","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5588-5235","authenticated-orcid":false,"given":"Roberto","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda","family":"Corrado","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Bioscience, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Gemignani","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-6357","authenticated-orcid":false,"given":"Stefano","family":"Landi","sequence":"additional","affiliation":[{"name":"Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1183\/09031936.96.09091932","article-title":"The epidemiology of mesothelioma in historical context","volume":"9","author":"McDonald","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.2471\/BLT.11.086678","article-title":"Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008","volume":"89","author":"Delgermaa","year":"2011","journal-title":"Bull. World Health Organ."},{"key":"ref_3","first-page":"491","article-title":"Malignant pleural mesothelioma: An epidemiological perspective","volume":"1","author":"Robinson","year":"2012","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ctrv.2014.10.007","article-title":"Malignant pleural mesothelioma: New hope in the horizon with novel therapeutic strategies","volume":"41","author":"Remon","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.mrrev.2011.12.003","article-title":"A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma","volume":"750","author":"Melaiu","year":"2012","journal-title":"Mutat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.mrfmmm.2014.11.002","article-title":"Expression status of candidate genes in mesothelioma tissues and cell lines","volume":"771","author":"Melaiu","year":"2015","journal-title":"Mutat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.advms.2018.08.018","article-title":"Metabolic pathways of L-arginine and therapeutic consequences in tumors","volume":"64","author":"Szefel","year":"2018","journal-title":"Adv. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.mod.2005.04.002","article-title":"Functional diversity of the eukaryotic translation initiation factors belonging to eIF4 families","volume":"122","year":"2005","journal-title":"Mech. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R49","DOI":"10.1530\/ERC-16-0569","article-title":"Glycosylation is a global target for androgen control in prostate cancer cells","volume":"24","author":"Munkley","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"198","DOI":"10.2337\/diacare.13.3.198","article-title":"Molecular biology of mammalian glucose transporters","volume":"13","author":"Bell","year":"1990","journal-title":"Diabetes Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4217259","DOI":"10.1155\/2018\/4217259","article-title":"The Roles of Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 in Cancer and Cancer Stem Cells","volume":"2018","author":"Cao","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.jbior.2012.03.004","article-title":"The newcomer in the integrin family: Integrin \u03b19 in biology and cancer","volume":"52","author":"Couchman","year":"2012","journal-title":"Adv. Biol. Regul."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1242\/jcs.03071","article-title":"Ran at a glance","volume":"119","author":"Joseph","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.18632\/genesandcancer.4","article-title":"SOD1, an unexpected novel target for cancer therapy","volume":"5","author":"Papa","year":"2014","journal-title":"Genes Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1046\/j.1087-0024.2000.00005.x","article-title":"Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis","volume":"5","author":"Bornstein","year":"2000","journal-title":"J. Investig Derm. Symp. Proc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1309\/AJCP5KNL7QTELLYI","article-title":"Comparative immunohistochemical analysis of IMP3, GLUT1, EMA, CD146, and desmin for distinguishing malignant mesothelioma from reactive mesothelial cells","volume":"141","author":"Minato","year":"2014","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jamaoncol.2016.3049","article-title":"Arginine Deprivation with Pegylated Arginine Deiminase in patients with Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial","volume":"3","author":"Szlosarek","year":"2017","journal-title":"Jama Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Barbone, D., Van Dam, L., Follo, C., Jithesh, P.V., Zhang, S., Richards, W.G., Bueno, R., Fennell, D.A., and Broaddus, V.C. (2016). Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150044"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"662","DOI":"10.3389\/fonc.2018.00662","article-title":"Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability","volume":"8","author":"Sheng","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1021\/cb2000296","article-title":"Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-\u03b2","volume":"6","author":"Soderholm","year":"2011","journal-title":"ACS Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25882","DOI":"10.1074\/jbc.M110.178012","article-title":"Insulin Growth factor-2 Binding Protein 3 (IGF2BP3) Is a Glioblastoma-Specific Marker That Activates Phosphatidylinositol 3-kinase\/mitogen-activated Protein Kinase (PI3K\/MAPK) Pathways by Modulating IGF-2","volume":"286","author":"Suvasini","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1007\/s12094-015-1280-4","article-title":"Expression of IMP3 and IGF2 in Giant Cell Tumor of Spine Is Associated With Tumor Recurrence and Angiogenesis","volume":"17","author":"Zhang","year":"2015","journal-title":"Clin. Transl. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/ijc.10180","article-title":"Overexpression of the eukaryotic translation Initiation Factor 4G (eIF4G-1) in squamous cell lung carcinoma","volume":"98","author":"Bauer","year":"2002","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/1476-4598-9-78","article-title":"Over-expression of eukaryotic translation initiation factor 4 gamma 1 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma","volume":"9","author":"Tu","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24242","DOI":"10.18632\/oncotarget.8168","article-title":"Functional role of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in NSCLC","volume":"7","author":"Cao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7459","DOI":"10.1038\/s41598-018-25798-7","article-title":"Eukaryotic Translation Initiation Factor 4 Gamma 1 (eIF4G1) is upregulated during Prostate cancer progression and modulates cell growth and metastasis","volume":"8","author":"Jaiswal","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1002\/1878-0261.12384","article-title":"Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling","volume":"12","author":"Shen","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1182\/blood-2009-09-220020","article-title":"Targeting the translational machinery as a novel treatment strategy for hematologic malignancies","volume":"115","author":"Hagner","year":"2010","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/s12935-019-0947-2","article-title":"Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): A Target for Cancer Therapeutic Intervention?","volume":"19","author":"Jaiswal","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1158\/0008-5472.CAN-07-5279","article-title":"Tumor cell dependence on Ran-GTP-directed mitosis","volume":"68","author":"Xia","year":"2008","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.bbrc.2013.09.079","article-title":"Ran GTPase protein promotes human pancreatic cancer proliferation by deregulating the expression of Survivin and cell cycle proteins","volume":"440","author":"Deng","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1007\/s10147-012-0465-x","article-title":"High Ran level is correlated with poor prognosis in patients with colorectal cancer","volume":"18","author":"Fan","year":"2013","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3727\/096504013X13747716581417","article-title":"Ran GTPase induces EMT and enhances invasion in non-small cell lung cancer cells through activation of PI3K-AKT pathway","volume":"21","author":"Ning","year":"2013","journal-title":"Oncol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s11523-016-0432-y","article-title":"Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer","volume":"11","author":"Vaidyanathan","year":"2016","journal-title":"Target. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5565","DOI":"10.1111\/jcmm.15213","article-title":"PRMT5 Silencing Selectively Affects MTAP-deleted Mesothelioma: In Vitro Evidence of a Novel Promising Approach","volume":"24","author":"Barbarino","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"438","DOI":"10.18632\/genesandcancer.129","article-title":"Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines","volume":"8","author":"Melaiu","year":"2017","journal-title":"Genes Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/4856\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:19Z","timestamp":1760176159000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/4856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,9]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21144856"],"URL":"https:\/\/doi.org\/10.3390\/ijms21144856","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,9]]}}}