期刊
CANCERS
卷 14, 期 14, 页码 -出版社
MDPI
DOI: 10.3390/cancers14143509
关键词
ERK5; MAPK7; soft tissue sarcoma; leiomyosarcoma; rhabdomyosarcoma; KLF2; 3-methyl-cholanthrene
类别
资金
- MCIN/AEI, ERDF A way of making Europe [RTI2018-094093-B-I00]
- Fundacion Leticia Castillejo Castillo
- Roche Espana
- ACEPAIN
- European Community through the FEDER
- University of Castilla-La Mancha (UCLM)
- European Social Fund (FSE) through its Operative Program for Castilla-La Mancha (2007-2013)
ERK5 plays a critical role in the biology of soft tissue sarcoma, as shown in both mouse models and human sarcomas. Transcriptome analysis reveals the important role of KLF2 in the biological effects of ERK5. These findings open new avenues for the diagnosis and therapy of soft tissue sarcomas.
Simple Summary 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.
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