title: MAPK pathways regulation by DUSP1 in the development of osteosarcoma: Potential markers and therapeutic targets.
abstract: Osteosarcoma (OS) is the most frequent primary bone tumor that affect children and adolescents. This tumor is highly aggressive with high risk of metastasis and the implementation of new drugs has not been successful. The search for biomarkers or new therapeutic targets is urgently needed and can help in advances of OS treatment. MAPKs are major signaling transduction molecules that play an important role in regulating a variety of cellular responses. DUSP1 is a phosphatase that dephosphorylates the MAPKs. Both MAPKs and DUSPs have been implicated as major modulators of critical signaling pathways that are dysregulated in various diseases. In a previous study, we found an increase in MAPK7 gene expression contributed for worst overall survival and treatment response. We analyzed gene expression of MAPK pathways that participate in MAPK7 regulation, and DUSP1 gene using paired 28 pre/post-chemotherapy and 12 metastasis OS samples. To understand the DUSP1 role in the pathogenesis of OS, we assessed the function of DUSP1 in four OS cell lines through a series of cellular assays combined with gene silencing technique. Our findings showed increased MAP2K6, MAP4K3, and DUSP1 gene expression in post-chemotherapy OS samples presenting poor prognosis. We also found that the suppression of DUSP1 gene expression resulted in decreased proliferation, migration, and invasion in OS cells. These results suggest that members of MAPK family may be possible prognostic markers in OS and DUSP1 has a relevant role in the OS pathogenesis and can be an attractive therapeutic target in new strategies of OS treatment.
authors.affiliation: Genetics Laboratory, Department of Pediatrics, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.|Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Luana Joyce Silva
authors.initials: LJS
authors.lastname: Lopes
authors.affiliation: Genetics Laboratory, Department of Pediatrics, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Francine
authors.initials: F
authors.lastname: Tesser-Gamba
authors.affiliation: Department of Pediatrics, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Antônio Sérgio
authors.initials: AS
authors.lastname: Petrilli
authors.affiliation: Department of Pathology, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: de Seixas Alves
authors.affiliation: Department of Orthopedic Surgery and Traumatology, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Reynaldo Jesus
authors.initials: RJ
authors.lastname: Garcia-Filho
authors.affiliation: Genetics Laboratory, Department of Pediatrics, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Federal University of São Paulo, São Paulo, Brazil.|Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, Brazil.|Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Silvia Regina Caminada
authors.initials: SRC
authors.lastname: Toledo
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D048669:MAP Kinase Kinase 6 / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D012516:Osteosarcoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C543044:MAP4K3 protein, human; D017346:Protein Serine-Threonine Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: DUSP1; MAPK signaling pathways; biomarkers; osteosarcoma; therapeutic target