The signalling axis ERK5/KLF2 is a major determinant of chemical sarcomagenesis

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this particular 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, colony-forming capacity, and caused a marked loss of tumor growth in vivo. Indeed, the transcriptomic profile in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration or motility, among others. Finally, among the various differentially expressed genes, Klf2, a direct target of the ERK5 pathway, is a key mediator of the biological effects of ERK5 in vitro and in vivo, as indicated by its specific interference. Therefore, our data suggest that the ERK5KLF2 signaling axis is an important determinant of 3MC-induced sarcomas and should be further studied in human sarcomas, especially those of muscular origin. mRNA profile of Ek5-defficient/prficiebt 3MC-induced tumor cell lines