{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T07:22:32Z","timestamp":1778916152902,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,6]],"date-time":"2020-06-06T00:00:00Z","timestamp":1591401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["CDR"],"award-info":[{"award-number":["CDR"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["T\u00e9l\u00e9vie"],"award-info":[{"award-number":["T\u00e9l\u00e9vie"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Belgian Foundation against Cancer","award":["Asbestos grants"],"award-info":[{"award-number":["Asbestos grants"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I\/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V\/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB\/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGF\u03b1) was associated with resistance to this regimen. The silencing of TGF\u03b1 by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGF\u03b1 desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGF\u03b1 receptor (epidermal growth factor receptor\/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGF\u03b1 expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGF\u03b1 but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.<\/jats:p>","DOI":"10.3390\/cancers12061484","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T06:34:16Z","timestamp":1591684456000},"page":"1484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["TGF\u03b1 Promotes Chemoresistance of Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"12","author":[{"given":"Bernard","family":"Staumont","sequence":"first","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Majeed","family":"Jamakhani","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrisostome","family":"Costa","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Vandermeers","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sathya Neelature","family":"Sriramareddy","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ga\u00eblle","family":"Redout\u00e9","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Mascaux","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Strasbourg University Hospital, 67091 Strasbourg, France"},{"name":"Interface de Recherche Fondamentale et Appliqu\u00e9e en Canc\u00e9rologie, INSERM U1113, Universit\u00e9 de Strasbourg, 67200 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Delvenne","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Hubert","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology, GIGA-Cancer, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roghaiyeh","family":"Safari","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0563-2213","authenticated-orcid":false,"given":"Luc","family":"Willems","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (GxABT), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nrc.2017.42","article-title":"Novel insights into mesothelioma biology and implications for therapy","volume":"17","author":"Yap","year":"2017","journal-title":"Nat. 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