ERK5 Is a Major Determinant of Chemical Sarcomagenesis : Implications in Human Pathology
Arconada-Luque, Elena (Centro Regional de Investigaciones Biomédicas)
Jiménez-Suarez, Jaime (Centro Regional de Investigaciones Biomédicas)
Pascual-Serra, Raquel (Centro Regional de Investigaciones Biomédicas)
Nam-Cha, Syong Hyun (Complejo Hospitalario Universitario de Albacete)
Moliné, Teresa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Cimas, Francisco J. (Universidad de Castilla-La Mancha)
Fliquete, Germán (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ortega-Muelas, Marta (Centro Regional de Investigaciones Biomédicas)
Roche, Olga (Universidad de Castilla-La Mancha)
Fernández-Aroca, Diego M. (Centro Regional de Investigaciones Biomédicas)
Muñoz Velasco, Raúl (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
García-Flores, Natalia (Centro Regional de Investigaciones Biomédicas)
Garnés-García, Cristina (Centro Regional de Investigaciones Biomédicas)
Sánchez-Fdez, Adrián (Centro de Investigación Biomédica en Red de Cáncer)
Matilla-Almazán, Sofía (Centro de Investigación Biomédica en Red de Cáncer)
Sánchez-Arévalo Lobo, Víctor J. (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Hernandez-Losa, Javier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Belandia, Borja (Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM))
Pandiella, Atanasio (Centro de Investigación Biomédica en Red de Cáncer)
Esparís-Ogando, Azucena (Centro de Investigación Biomédica en Red de Cáncer)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Institut de Recerca)
del Peso, Luis (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias)
Sánchez-Prieto, Ricardo (Instituto de Investigaciones Biomédicas 'Alberto Sols')
Ruiz-Hidalgo, María José (Universidad de Castilla-La Mancha)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	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. 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.
Grants:	Agencia Estatal de Investigación RTI2018-094093-B-I00
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	ERK5 ; KLF2 ; Leiomyosarcoma ; MAPK7 ; Rhabdomyosarcoma ; Soft tissue sarcoma ; 3-methyl-cholanthrene
Published in:	Cancers, Vol. 14 (july 2022) , ISSN 2072-6694

DOI: 10.3390/cancers14143509
PMID: 35884568

19 p, 9.2 MB

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