<p>Identification of key genes and pathways in Ewing’s sarcoma patients associated with metastasis and poor prognosis</p>

Abstract

Background: Ewing sarcoma (ES) is the second commonest primary malignant bone neoplasm. Metastatic status at diagnosis strongly predicted poor prognosis of Ewing sarcoma patients. Yet little was known about the underlying mechanism of ES metastasis. Purpose: This study intended to identify the relationship between key genes/pathways and metastasis/poor prognosis in Ewing's sarcoma patients by using bioinformatic method. Methods: In this study, multi-center sequencing data were obtained from the GEO database, including gene and miRNA expression profile and prognosis information of ES patients. Differentially expressed genes (DEGs) were identified between primary and metastasis ES samples by the GEO2R online tool. Gene ontology (Go) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses of DEGs were performed. And PPI network analyses were conducted. The ES patient’s prognostic information was employed for survival analysis, and the potential relationship between miRNAs and key genes was analyzed. Results: The results showed that a total of 298 and 428 DEGs were screened out in metastasis samples based on GSE17618 and GSE12102 dataset compared to primary samples respectively. The most significantly enriched KEGG pathway was the mismatch repair (MMR) pathway. MSH2, MSH6, RPA2, and RFC2 that belong to the MMR pathway were identified as key genes. Moreover, the expression of key genes was increased in metastasis samples compared with primary ones and was associated with poor event-free and overall survival of ES patients. The negative correlation of the expression level of the key genes with patients prognosis also supported by TCGA sarcoma database. Furthermore, knockdown of EWSR/FLI1 fusion in ES cell line A673 down-regulates the expression of the 4 key genes was revealed by GDS4962. Conclusion: In conclusion, the present study indicated that the key genes promote our understanding of the molecular mechanisms underlying the development of ES metastasis, and might be used as molecular targets and diagnostic biomarkers for the treatment of ES.

Exosomes in Bone Sarcomas: Key Players in Metastasis

“…Moreover, different novel treatment strategies are evaluating their efficacy in OS metastatic patients through clinical trials [75], with the aim of finding novel treatment strategies for these patients. In ES, similar studies have resulted in several genes linked to metastasis, such as ROR1 [80], MSH2, MSH6, RPA2, and RFC2 genes from the mismatch repair pathway [81], PPP1R1A [82] and TWIST1 proteins [83], the Cad11 adhesion molecule [84], or ERBB4 via activation of the PI3K-Akt-FAK cascade [85]. Moreover, similar to other cancers, hypoxia has been associated with induction of metastasis in OS and ES via regulation of HIF1α through HIF1α [86] or overexpression of CXCR4 in ES [87], amongst others.…”

YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells

“…Moreover, fluctuations in EWS-FLI1 levels are not the only mechanism known to initiate EwS dissemination 51 , and several candidates such as chemokine receptor CXCR4 signalling 52 , chromatin modifiers 53 , cadherins 54 , micro-RNAs 55 and interactions with the tumour microenvironment including glucocorticoids 56,57 have been proposed. In our in vivo proof-of-principle experiments, reduction in onset and number of lung metastases depending on dose and timing of VP treatment did not achieve statistical significance.…”

DNA Repair Defects in Sarcomas

“…The findings highlighted the MMR pathway as the most significantly enriched KEGG pathway in EWS patients [73]. The expression levels of key MMR components including MSH2 and MSH6 are found to be significantly associated with metastasis, shorter EFS, and overall poor prognosis in Ewing sarcoma patients [73]. Several studies have investigated the role of MMR pathway in osteosarcoma.…”

“…A study conducted by Li et al, emphasized the importance of MMR pathway in Ewing sarcoma and showed that the expression levels of MSH2 and MSH6 is correlated with an increased chance of metastasis and poor prognosis in these patients [73]. They used the GEO database to investigate the correlation of the key dysregulated genes and pathways with prognosis information and metastasis status of the Ewing sarcoma patients [73]. The findings highlighted the MMR pathway as the most significantly enriched KEGG pathway in EWS patients [73].…”

“…They used the GEO database to investigate the correlation of the key dysregulated genes and pathways with prognosis information and metastasis status of the Ewing sarcoma patients [73]. The findings highlighted the MMR pathway as the most significantly enriched KEGG pathway in EWS patients [73]. The expression levels of key MMR components including MSH2 and MSH6 are found to be significantly associated with metastasis, shorter EFS, and overall poor prognosis in Ewing sarcoma patients [73].…”