Gene expression of the MAPK pathway in osteosarcoma.

Abstract

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.

Bone and Extracellular Signal-Related Kinase 5 (ERK5)

“…Moreover, ERK5 serves as a valuable marker for assessing treatment and prognosis in osteosarcoma [191]. Lopes et al observed overexpression of the ERK5 gene in pre-chemotherapy samples compared to post-treatment and normal bone specimens, associating high ERK5 expression with adverse therapeutic outcomes and lower survival rates in osteosarcoma patients [192]. Numerous studies corroborate the therapeutic potential of targeting ERK5 in various malignancies [193,194].…”