{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:49:35Z","timestamp":1787989775475,"version":"build-2784847793"},"reference-count":37,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006692","name":"Italian Ministry of University and Research","doi-asserted-by":"publisher","award":["ALDE_RILO_19_01"],"award-info":[{"award-number":["ALDE_RILO_19_01"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure. MPM pathogenesis has been related both to oxidative stress, evoked by and in response to asbestos fibers exposure, and epithelial mesenchymal transition (EMT), an event induced by oxidative stress itself and related to cancer proliferation and metastasis. Asbestos-related primary oxidative damage is counteracted in the lungs by various redox-sensitive factors, often hyperactivated in some cancers. Among these redox-sensitive factors, Apurinic-apyrimidinic endonuclease 1 (APE-1)\/Redox effector factor 1 (Ref-1) has been demonstrated to be overexpressed in MPM and lung cancer, but the molecular mechanism has not yet been fully understood. Moreover, asbestos exposure has been associated with induced EMT events, via some EMT transcription factors, such as Twist, Zeb-1 and Snail-1, in possible crosstalk with oxidative stress and inflammation events. To demonstrate this hypothesis, we inhibited\/silenced Ref-1 in MPM cells; as a consequence, both EMT (Twist, Zeb-1 and Snail-1) markers and cellular migration\/proliferation were significantly inhibited. Taken as a whole, these results show, for the first time, crosstalk between oxidative stress and EMT in MPM carcinogenesis and invasiveness, thus improving the knowledge to better address a preventive and therapeutic approach against this aggressive cancer.<\/jats:p>","DOI":"10.3390\/ijms241612570","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:26:39Z","timestamp":1691497599000},"page":"12570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["APE-1\/Ref-1 Inhibition Blocks Malignant Pleural Mesothelioma Cell Proliferation and Migration: Crosstalk between Oxidative Stress and Epithelial Mesenchymal Transition (EMT) in Driving Carcinogenesis and Metastasis"],"prefix":"10.3390","volume":"24","author":[{"given":"Valeria","family":"Ramundo","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Zanirato","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Palazzo","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-4836","authenticated-orcid":false,"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0236-6175","authenticated-orcid":false,"given":"Elisabetta","family":"Aldieri","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Torino, 10126 Torino, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Torino, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.3389\/fonc.2019.01519","article-title":"Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future","volume":"9","author":"Nicolini","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"924","DOI":"10.21037\/tlcr.2020.03.38","article-title":"Clinical Significance of Histologic Subtyping of Malignant Pleural Mesothelioma","volume":"9","author":"Brcic","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1183\/16000617.0063-2016","article-title":"Malignant Pleural Mesothelioma: An Update on Investigation, Diagnosis and Treatment","volume":"25","author":"Bibby","year":"2016","journal-title":"Eur. Respir. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.trsl.2009.01.004","article-title":"Asbestos-Induced Lung Diseases: An Update","volume":"153","author":"Kamp","year":"2009","journal-title":"Transl. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ramundo, V., Zanirato, G., and Aldieri, E. (2021). The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma. IJMS, 22.","DOI":"10.3390\/ijms222212216"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.freeradbiomed.2015.05.002","article-title":"Malignant Mesothelioma as an Oxidative Stress-Induced Cancer: An Update","volume":"86","author":"Chew","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s10555-016-9648-7","article-title":"EMT, Cell Plasticity and Metastasis","volume":"35","author":"Chaffer","year":"2016","journal-title":"Cancer Metastasis Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41580-018-0080-4","article-title":"New Insights into the Mechanisms of Epithelial\u2013Mesenchymal Transition and Implications for Cancer","volume":"20","author":"Dongre","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1089\/ars.2009.2737","article-title":"Epithelial\u2013Mesenchymal Transition: From Molecular Mechanisms, Redox Regulation to Implications in Human Health and Disease","volume":"12","author":"Cannito","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_10","first-page":"154","article-title":"Epithelial mesenchymal transition and lung cancer","volume":"2","author":"Xiao","year":"2010","journal-title":"J. Thorac. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Legras, A., P\u00e9cuchet, N., Imbeaud, S., Pallier, K., Didelot, A., Roussel, H., Gibault, L., Fabre, E., Le Pimpec-Barthes, F., and Laurent-Puig, P. (2017). Epithelial-to-Mesenchymal Transition and MicroRNAs in Lung Cancer. Cancers, 9.","DOI":"10.3390\/cancers9080101"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12032-017-0900-y","article-title":"Epithelial Mesenchymal Transition (EMT) and Non-Small Cell Lung Cancer (NSCLC): A Mutual Association with Airway Disease","volume":"34","author":"Mahmood","year":"2017","journal-title":"Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.ejcts.2009.08.027","article-title":"Prognostic Significance of Epithelial\u2013Mesenchymal Transition in Malignant Pleural Mesothelioma","volume":"37","author":"Schramm","year":"2010","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/s41598-022-04973-x","article-title":"A Panel of Emerging EMT Genes Identified in Malignant Mesothelioma","volume":"12","author":"Wu","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Turini, S., Bergandi, L., Gazzano, E., Prato, M., and Aldieri, E. (2019). Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-\u03b2 as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event. IJMS, 20.","DOI":"10.3390\/ijms20010150"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000356874","article-title":"Clinical Significance of Epithelial-Mesenchymal Transition-Associated Markers in Malignant Pleural Mesothelioma","volume":"86","author":"Iwanami","year":"2014","journal-title":"Oncology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.3892\/ijo.2014.2310","article-title":"JAK\/STAT3 Signaling Is Required for TGF-\u03b2-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells","volume":"44","author":"Liu","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.3892\/mmr.2014.2279","article-title":"HSP70 Inhibits High Glucose-Induced Smad3 Activation and Attenuates Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells","volume":"10","author":"Liu","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2013). Hydrogen Peroxide Promotes Epithelial to Mesenchymal Transition and Stemness in Human Malignant Mesothelioma Cells. Asian Pac. J. Cancer Prev., 14, 3625\u20133630.","DOI":"10.7314\/APJCP.2013.14.6.3625"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.freeradbiomed.2011.12.020","article-title":"Free Radical Generation Induces Epithelial-to-Mesenchymal Transition in Lung Epithelium via a TGF-\u03921-Dependent Mechanism","volume":"52","author":"Gorowiec","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Schiavello, M., Gazzano, E., Bergandi, L., Silvagno, F., Libener, R., Riganti, C., and Aldieri, E. (2021). Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma. Cancers, 13.","DOI":"10.3390\/cancers13051138"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.lungcan.2009.02.019","article-title":"APE1 Overexpression Is Associated with Cisplatin Resistance in Non-Small Cell Lung Cancer and Targeted Inhibition of APE1 Enhances the Activity of Cisplatin in A549 Cells","volume":"66","author":"Wang","year":"2009","journal-title":"Lung Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.drudis.2020.10.015","article-title":"The Multifunctional APE1 DNA Repair\u2013Redox Signaling Protein as a Drug Target in Human Disease","volume":"26","author":"Caston","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41698-017-0023-0","article-title":"Exploiting the Ref-1-APE1 Node in Cancer Signaling and Other Diseases: From Bench to Clinic","volume":"1","author":"Shah","year":"2017","journal-title":"NPJ Precis. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1158\/1535-7163.679.3.6","article-title":"Human Apurinic Endonuclease 1 (APE1) Expression and Prognostic Significance in Osteosarcoma: Enhanced Sensitivity of Osteosarcoma to DNA Damaging Agents Using Silencing RNA APE1 Expression Inhibition","volume":"3","author":"Wang","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/cgt.2008.30","article-title":"Chimeric Adenoviral Vector Ad5\/F35-Mediated APE1 SiRNA Enhances Sensitivity of Human Colorectal Cancer Cells to Radiotherapy in vitro and in vivo","volume":"15","author":"Xiang","year":"2008","journal-title":"Cancer Gene Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"296","DOI":"10.3816\/CLM.2007.n.006","article-title":"Experimental Study Enhancing the Chemosensitivity of Multiple Myeloma to Melphalan by Using a Tissue-Specific APE1-Silencing RNA Expression Vector","volume":"7","author":"Yang","year":"2007","journal-title":"Clin. Lymphoma Myeloma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/modpathol.2011.144","article-title":"Epithelial\u2013Mesenchymal Transition in Malignant Mesothelioma","volume":"25","author":"Fassina","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-0463.2012.02931.x","article-title":"Expression of Snail, Twist, and Zeb1 in Malignant Mesothelioma","volume":"121","author":"Merikallio","year":"2013","journal-title":"APMIS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10555-015-9563-3","article-title":"Epigenetics in Lung Cancer Diagnosis and Therapy","volume":"34","author":"Mehta","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41568-021-00435-0","article-title":"The Role of ROS in Tumour Development and Progression","volume":"22","author":"Cheung","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.joms.2018.11.034","article-title":"Apurinic\/Apyrimidinic Endonuclease 1\/Redox Factor-1 Could Serve as a Potential Serological Biomarker for the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma","volume":"77","author":"Xie","year":"2019","journal-title":"J. Oral. Maxillofac. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1186\/s13046-021-02046-x","article-title":"Ref-1 Redox Activity Alters Cancer Cell Metabolism in Pancreatic Cancer: Exploiting This Novel Finding as a Potential Target","volume":"40","author":"Gampala","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jdermsci.2020.08.012","article-title":"APE1 Promotes Proliferation and Migration of Cutaneous Squamous Cell Carcinoma","volume":"100","author":"Deng","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1002\/cam4.1717","article-title":"The Regulatory Role of APE1 in Epithelial-to-Mesenchymal Transition and in Determining EGFR-TKI Responsiveness in Non-Small-Cell Lung Cancer","volume":"7","author":"Yang","year":"2018","journal-title":"Cancer Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s11748-021-01595-4","article-title":"Lung Cancer and Epithelial-Mesenchymal Transition","volume":"69","author":"Menju","year":"2021","journal-title":"Gen. Thorac. Cardiovasc. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1158\/1535-7163.MCT-18-1166","article-title":"Antitumor Activity and Mechanistic Characterization of APE1\/Ref-1 Inhibitors in Bladder Cancer","volume":"18","author":"Fishel","year":"2019","journal-title":"Mol. Cancer Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:28:05Z","timestamp":1760128085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":37,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612570"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612570","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,8]]}}}