Osteosarcoma is the most common type of malignant bone cancer, which often affects teenagers and young adults. The present study aimed to screen for critical genes and microRNAs (miRNAs/miRs) involved in osteosarcoma. A total of four microarray datasets (accession numbers GSE32981, GSE21257, GSE14827 and GSE14359) were downloaded from the Gene Expression Omnibus database. Following data preprocessing, module analysis was performed to identify the stable modules using the weighted gene co-expression network analysis (WGCNA) package. The differentially expressed genes (DEGs) between metastatic samples and non-metastatic samples were screened, followed by gene co-expression network construction, and Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Subsequently, prognosis-associated genes were screened and a miRNA-target gene regulatory network was constructed. Finally, the data for critical genes were validated. WGCNA analysis identified six modules; blue and yellow modules were significantly positively associated with osteosarcoma metastasis. A total of 1,613 DEGs were screened between primary tissue samples and metastatic samples. Following comparison of the genes in the two (blue and yellow) modules, a total of 166 DEGs were identified (metastatic samples vs. non-metastatic samples). Functional enrichment analysis demonstrated that these DEGs were mainly involved in ‘defense response’, ‘p53 signaling pathway’ and ‘lysosome’. By utilizing the clinical information in GSE21257, 10 critical genes associated with osteosarcoma prognosis were obtained, including CTP synthase 2 ( CTPS2 ), tumor protein p53 inducible protein 3 ( TP53I3 ) and solute carrier family 1 member 1 ( SLC1A1 ). In addition, hsa-miR-422a and hsa-miR-194 were highlighted in the miRNA-target gene network. Finally, matrix metallopeptidase 3 ( MMP3 ) and vascular endothelial growth factor B ( VEGFB ) were predicted as critical genes in osteosarcoma metastasis. CTPS2, TP53I3 and SLC1A1 may serve major roles in osteosarcoma development, and hsa-miR-422a, hsa-miR-194, MMP3 and VEGFB may be associated with osteosarcoma metastasis.
Cyclooxygenase‐2 (COX‐2), a key enzyme in arachidonic acid metabolism, is involved in several cancers, including osteosarcoma. The prognostic significance of COX‐2 in osteosarcoma remains controversial. This study was to analyze the potential clinical and prognostic effects of COX‐2 protein expression in patients with osteosarcoma. Eligible articles were searched via online databases. The combined odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were calculated using the random‐effects model. Trial sequential analysis (TSA) was applied to analyze the required information size and determine the reliability of the evidence. Twenty‐three studies on COX‐2 expression were identified, which included a total of 1084 patients with malignant osteosarcoma and 247 patients with benign osteochondroma. COX‐2 protein expression in osteosarcoma was higher than in benign osteochondroma (OR = 7.66, P < 0.001). COX‐2 expression was not correlated with age, gender, tumor location, cancer histology, or necrosis (P > 0.1), but was significantly associated with tumor grade (high grade vs. low grade: OR = 4.81, P < 0.001), clinical stage (stage 3–4 vs. stage 1–2: OR = 4.89, P < 0.001), and metastasis (yes vs. no: OR = 3.53, P < 0.001). Based on TSA results, we suggest that additional studies are not required to examine osteosarcoma vs. benign osteochondroma, tumor grade, clinical stage, or metastasis. No heterogeneity was observed in these analyses. COX‐2 expression is linked to poor prognosis in metastasis‐free survival, overall survival, and relapse‐free survival, as indicated by multivariate analysis. Therefore, the expression of COX‐2 may correlate with the development, progression, metastasis, and poor prognosis of osteosarcoma.
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