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.
10534 Background: Osteosarcoma (OS) is the most common malignant bone tumor in adolescents. A feature of the OS is its high risk of lung metastasis. Unlike other sarcomas, OS does not have genetic markers. We suggest that abnormalities in the expression levels of genes involved in important cell signaling pathways, as MAPKs pathway, may contribute to OS progression and aggressiveness. In a recent study, we found an overexpression of MAPK7 gene in prechemotherapy specimens when compared to postchemotherapy specimens and when compared with normal bone. This previous study suggests that MAPK7 overexpression may be contributing to the worse response to treatment and therefore a poor overall survival. To understand the relationship between the OS genesis process and the MAPK pathway, we investigated the expression of genes involved in the regulation of MAPK pathway (MAP2K5, MAP2K6, MAP3K1, MAP3K3, MAP4K3 and DUSP1). Methods: Total RNA was extracted from 68 tumor samples obtained from 28 patients (28 prechemotherapy specimens, 28 postchemotherapy specimens and 12 metastasis specimens) and five normal bone tissues. cDNA was synthesized and expression of the six genes were determined by quantitative real-time PCR. Clinical variables were correlated with gene expression. Results: MAP2K6 and MAP4K3 had a similar gene expression profile. Both genes were overexpressed in postchemotherapy specimens and were strongly associated with important clinical parameters as presence of metastasis (P=0.0159 and P=0.0014, respectively), shorter overall survival (P=0.0040 and P=0.0040, respectively) and disease progression (P=0.0142 and P=0.0109, respectively). DUSP1 overexpression in postchemotherapy specimens was related with metastasis at diagnosis (P=0.0004), worse response to treatment (P=0.0009) and disease recurrence (P=0.0039). MAP2K5, MAP3K1 e MAP3K3 showed no significant correlations in the present study. Conclusions: The overexpression of MAP2K6, MAP4K3 and DUSP1 in postchemotherapy specimens presented a significant association with poor prognosis. The current study suggests that these genes could play an important role in OS tumorigenesis and may be in the future new therapeutic targets in OS treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.