The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum s...

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Autores principales:	Dennis M. Timmerman, Thomas F. Eleveld, Ad J. M. Gillis, Carlijn C. Friedrichs, Sanne Hillenius, Tessa L. Remmers, Sruthi Sriram, Leendert H. J. Looijenga
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	human malignant germ cell tumors mediastinal germ cell tumors testicular germ cell tumors cisplatin resistance <i>TP53</i> NCCIT Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/e3ff7794ad124071bdac71a905542ee0
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spelling	oai:doaj.org-article:e3ff7794ad124071bdac71a905542ee02021-11-11T17:14:01ZThe Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors10.3390/ijms2221117741422-00671661-6596https://doaj.org/article/e3ff7794ad124071bdac71a905542ee02021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11774https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with <i>TP53</i> mutations most often localize to the mediastinum. To elucidate the underlying mechanism, <i>TP53</i> knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type <i>TP53</i> testicular GCT) and NCCIT cell line (hemizygously mutated <i>TP53</i>, mutant <i>TP53</i> mediastinal GCT). The full knock-out of <i>TP53</i> in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that <i>TP53</i> mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the <i>TP53</i> mutant and mediastinal GCTs.Dennis M. TimmermanThomas F. EleveldAd J. M. GillisCarlijn C. FriedrichsSanne HilleniusTessa L. RemmersSruthi SriramLeendert H. J. LooijengaMDPI AGarticlehuman malignant germ cell tumorsmediastinal germ cell tumorstesticular germ cell tumorscisplatin resistance<i>TP53</i>NCCITBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11774, p 11774 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	human malignant germ cell tumors mediastinal germ cell tumors testicular germ cell tumors cisplatin resistance <i>TP53</i> NCCIT Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	human malignant germ cell tumors mediastinal germ cell tumors testicular germ cell tumors cisplatin resistance <i>TP53</i> NCCIT Biology (General) QH301-705.5 Chemistry QD1-999 Dennis M. Timmerman Thomas F. Eleveld Ad J. M. Gillis Carlijn C. Friedrichs Sanne Hillenius Tessa L. Remmers Sruthi Sriram Leendert H. J. Looijenga The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
description	Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with <i>TP53</i> mutations most often localize to the mediastinum. To elucidate the underlying mechanism, <i>TP53</i> knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type <i>TP53</i> testicular GCT) and NCCIT cell line (hemizygously mutated <i>TP53</i>, mutant <i>TP53</i> mediastinal GCT). The full knock-out of <i>TP53</i> in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that <i>TP53</i> mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the <i>TP53</i> mutant and mediastinal GCTs.
format	article
author	Dennis M. Timmerman Thomas F. Eleveld Ad J. M. Gillis Carlijn C. Friedrichs Sanne Hillenius Tessa L. Remmers Sruthi Sriram Leendert H. J. Looijenga
author_facet	Dennis M. Timmerman Thomas F. Eleveld Ad J. M. Gillis Carlijn C. Friedrichs Sanne Hillenius Tessa L. Remmers Sruthi Sriram Leendert H. J. Looijenga
author_sort	Dennis M. Timmerman
title	The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
title_short	The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
title_full	The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
title_fullStr	The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
title_full_unstemmed	The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors
title_sort	role of <i>tp53</i> in cisplatin resistance in mediastinal and testicular germ cell tumors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e3ff7794ad124071bdac71a905542ee0
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The Role of <i>TP53</i> in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

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