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

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.

Etiopathogenic role of ERK5 signaling in sarcoma: prognostic and therapeutic implications

“…Several other lines of evidence suggest that the MEK5/ERK5 pathway may have a role in sarcomagenesis. For example, in a chemical carcinogenesis model of pleomorphic sarcoma with muscular differentiation, marked upregulation of ERK5 was observed, and ERK5 downregulation abrogated tumor growth 40 . Despite the differences between the sarcoma subtypes generated in the genetic and chemical carcinogenesis models, both studies demonstrate the contribution of the MEK5/ERK5 pathway to the pathophysiology of sarcoma.…”