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.

ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway

“…Osteosarcoma is the most common primary bone tumor in young adults [1,2] and frequently occurs in the femur (42%), tibia (19%), and humerus (10%) [3]. Since the 1970s, despite the use of multi-agent chemotherapy and improvement in surgical techniques, the 5-year overall survival rate of osteosarcoma remains approximately 60% [4].…”

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

“…Other notable pairs that we identified from the correlation and that were previously reported in the literature included DUSP1-MAPK7 (= 0.79) and DUSP1-MAPK8 (= 0.82). DUSP1 gene silencing has been shown to increase the expression of MAPK7 and MAPK8 transcripts in osteosarcoma cells suggesting reciprocal actions between them [65]. DUSP10 (MKP-5) has been well known to dephosphorylate MAPK8 (JNK) [66] and has also been implicated in immune function.…”

Bone Microenvironment and Osteosarcoma Metastasis

“…Paris saponin VII (PS VII), Delphinidin can effectively inhibit the activation of the MAPK/ERK signaling pathway and further suppress the OS invasion, migration and promote apoptosis, which indicates that MAPK/ERK signaling pathway is activated in OS [ 91 , 92 ]. Over expressions of MAP2K6, MAP4K3, and DUSP1 are correlated with poor clinical prognoses [ 93 ]. Inversely, patients with decreasing expression of MAP4K3 can achieve a better treatment effect [ 93 ].…”

“…Over expressions of MAP2K6, MAP4K3, and DUSP1 are correlated with poor clinical prognoses [ 93 ]. Inversely, patients with decreasing expression of MAP4K3 can achieve a better treatment effect [ 93 ]. Moreover, the expression of DUSP1, one of the protein phosphatases which inhibits MAPKs through dephosphorylation, is significantly increased in metastasis patients and post-chemotherapy patients, suggesting that DUSP1 gene is related to OS metastasis and drug resistance [ 93 ].…”

“…Inversely, patients with decreasing expression of MAP4K3 can achieve a better treatment effect [ 93 ]. Moreover, the expression of DUSP1, one of the protein phosphatases which inhibits MAPKs through dephosphorylation, is significantly increased in metastasis patients and post-chemotherapy patients, suggesting that DUSP1 gene is related to OS metastasis and drug resistance [ 93 ]. Continuously, there are some other cellular molecules, such as ONZIN, macrophage migration inhibitory factor (MIF) activates the MAPK/ERK signaling pathway via directly or indirectly phosphorylating ERK1/2 to promoting OS invasion and metastasis [ 94 , 95 ].…”