47ca52bfe493031634693fb9816c304a pmc_9316148.pdf f772ac303f779944fdad9e6ed3a16cfdb95bf343 pmc_9316148.pdf 2311e80594401784a150d1a9c56cae60912a635cdaf31fc73d2e783d6b263dca pmc_9316148.pdf Title: ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology Subject: 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. Keywords: ERK5; MAPK7; soft tissue sarcoma; leiomyosarcoma; rhabdomyosarcoma; KLF2;3-methyl-cholanthrene Author: Elena Arconada-Luque, 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 Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Jul 20 07:49:16 2022 CEST ModDate: Wed Jul 20 10:15:56 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 9672582 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DGBDNV+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 MOCBVF+VnURWPalladioL Type 1 Custom yes yes no 15 0 TPPDYQ+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 SYOYAP+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 VUHBCL+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes 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Adhesion Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: RNA Isolation, Reverse Transcription, and Real-Time Quantitative PCR (RT-qPCR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Histology and Immunohistochemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: RNA Sequencing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Functional Enrichment Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: In Silico Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Children: Item: Title: ERK5 Is Upregulated in 3MC-Induced Sarcoma and in Human Leiomyosarcoma Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: ERK5 Is a Major Determinant in the Biology of Sarcoma-Derived Cell Lines Induced by 3MC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: ERK5 Modulates Transcriptional Landscape in Sarcoma-Derived Cell Lines Induced by 3MC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: KLF2 Is a Critical Mediator of the Biological Effects of ERK5 in Sarcoma-Derived Cell Lines Induced by 3MC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Info: Title: ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology Author: Elena Arconada-Luque, 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 Subject: 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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Subtype: Link Rect: 312, 101, 349, 111 Annotation: Subtype: Link Rect: 59, 78, 96, 88 Annotation: Subtype: Link Rect: 457, 66, 495, 77 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 153, 710, 191, 721 Annotation: Subtype: Link Rect: 135, 676, 173, 687 Annotation: Subtype: Link Rect: 472, 652, 510, 664 Annotation: Subtype: Link Rect: 516, 652, 552, 664 Annotation: Subtype: Link Rect: 272, 629, 309, 640 Annotation: Subtype: Link Rect: 519, 606, 557, 617 Annotation: Subtype: Link Rect: 59, 596, 95, 606 Annotation: Subtype: Link Rect: 118, 561, 155, 571 Annotation: Subtype: Link Rect: 161, 561, 197, 571 Checksum: f90b3eeb Type: CRC32 Checksum: 47ca52bfe493031634693fb9816c304a Type: MD5 Checksum: f772ac303f779944fdad9e6ed3a16cfdb95bf343 Type: SHA-1