ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain

Servicio de Anatomía Patológica, Hospital General de Albacete, 02008 Albacete, Spain

Grupo de Patología Molecular Traslacional, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona Centro de Investigación Biomédica en RED de Cancer CIBERONC, 08035 Barcelona, Spain

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Unidad de Bioquímica y Biología Molecular, Servicio de Instrumentación Biomédica, Universidad de Castilla-La Mancha, 02008 Albacete, Spain

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Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain

⁶

Grupo de Oncología Molecular, Facultad de Ciencias Experimentales, Instituto de Investigación Biosanitaria, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain

⁷

Departamento de Anatomía Patológica, Instituto de Investigación Hospital 12 de Octubre, Av. Córdoba, s/n, 28041 Madrid, Spain

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Instituto de Biología Molecular y Celular del Cáncer-CSIC, 37007 Salamanca, Spain

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Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Universidad de Salamanca, CSIC, 37007 Salamanca, Spain

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Centro de Investigación Biomédica en RED de Cancer CIBERONC, 37007 Salamanca, Spain

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Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain

¹²

Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), 28029 Madrid, Spain

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Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain

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Centro de Investigación Biomédica en Red de Enfermedades Respiratorias CIBERES, 28029 Madrid, Spain

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Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas (IIBM-CSIC)-Universidad de Castilla-La Mancha, 02008 Albacete, Spain

¹⁶

Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain

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^†

These authors contributed equally to this work.

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Both senior authors have contributed by equal to this work.

Academic Editor: Domenico Andrea Campanacci

Cancers 2022, 14(14), 3509; https://doi.org/10.3390/cancers14143509

Received: 20 June 2022 / Revised: 11 July 2022 / Accepted: 16 July 2022 / Published: 19 July 2022

(This article belongs to the Special Issue Advances in Translational Research for Soft Tissue Sarcomas)

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Sarcoma is a heterogeneous group of tumors poorly studied with few therapeutic opportunities. Interestingly, the role of MAPKs still remains unclear in sarcomatous pathology. Here, we describe for the first time the critical role of ERK5 in the biology of soft tissue sarcoma by using in vitro and in vivo approaches in a murine experimental model of chemical sarcomagenesis. Indeed, our observations were extrapolated to a short series of human leiomyosarcoma and rhabdomyosarcomas. Furthermore, transcriptome analysis allows us to demonstrate the critical role of KLF2 in the biological effects of ERK5. Therefore, the data presented here open new windows in the diagnosis and therapy of soft tissue sarcomas.

Abstract

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology. View Full-Text

Keywords: ERK5; MAPK7; soft tissue sarcoma; leiomyosarcoma; rhabdomyosarcoma; KLF2; 3-methyl-cholanthrene

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Arconada-Luque, E.; Jiménez-Suarez, J.; Pascual-Serra, R.; Nam-Cha, S.H.; Moline, T.; Cimas, F.J.; Fliquete, G.; Ortega-Muelas, M.; Roche, O.; Fernández-Aroca, D.M.; Muñoz Velasco, R.; García-Flores, N.; Garnés-García, C.; Sánchez-Fdez, A.; Matilla-Almazán, S.; Sánchez-Arévalo Lobo, V.J.; Hernández-Losa, J.; Belandia, B.; Pandiella, A.; Esparís-Ogando, A.; Ramón y Cajal, S.; del Peso, L.; Sánchez-Prieto, R.; Ruiz-Hidalgo, M.J. ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology. Cancers 2022, 14, 3509. https://doi.org/10.3390/cancers14143509

AMA Style

Arconada-Luque E, Jiménez-Suarez J, Pascual-Serra R, Nam-Cha SH, Moline T, Cimas FJ, Fliquete G, Ortega-Muelas M, Roche O, Fernández-Aroca DM, Muñoz Velasco R, García-Flores N, Garnés-García C, Sánchez-Fdez A, Matilla-Almazán S, Sánchez-Arévalo Lobo VJ, Hernández-Losa J, Belandia B, Pandiella A, Esparís-Ogando A, Ramón y Cajal S, del Peso L, Sánchez-Prieto R, Ruiz-Hidalgo MJ. ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology. Cancers. 2022; 14(14):3509. https://doi.org/10.3390/cancers14143509

Chicago/Turabian Style

Arconada-Luque, Elena, Jaime Jiménez-Suarez, Raquel Pascual-Serra, Syong Hyun Nam-Cha, Teresa Moline, Francisco J. Cimas, Germán Fliquete, Marta Ortega-Muelas, Olga Roche, Diego M. Fernández-Aroca, Raúl Muñoz Velasco, Natalia García-Flores, Cristina Garnés-García, Adrián Sánchez-Fdez, Sofía Matilla-Almazán, Víctor J. Sánchez-Arévalo Lobo, Javier Hernández-Losa, Borja Belandia, Atanasio Pandiella, Azucena Esparís-Ogando, Santiago Ramón y Cajal, Luis del Peso, Ricardo Sánchez-Prieto, and María José Ruiz-Hidalgo. 2022. "ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology" Cancers 14, no. 14: 3509. https://doi.org/10.3390/cancers14143509

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ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

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