Identification of key genes in osteosarcoma by meta‑analysis of gene expression microarray

Abstract

Osteosarcoma (OS) is one of the most malignant tumors in children and young adults. To better understand the underlying mechanism, five related datasets deposited in the Gene Expression Omnibus were included in the present study. The Bioconductor ‘limma’ package was used to identify differentially expressed genes (DEGs) and the ‘Weighted Gene Co-expression Network Analysis’ package was used to construct a weighted gene co-expression network to identify key modules and hub genes, associated with OS. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes overrepresentation analyses were used for functional annotation. The results indicated that 1,405 genes were dysregulated in OS, including 927 upregulated and 478 downregulated genes, when the cut off value was set at a ≥2 fold-change and an adjusted P-value of P<0.01 was used. Functional annotation of DEGs indicated that these genes were involved in the extracellular matrix (ECM) and that they function in several processes, including biological adhesion, ECM organization, cell migration and leukocyte migration. These findings suggested that dysregulation of the ECM shaped the tumor microenvironment and modulated the OS hallmark. Genes assigned to the yellow module were positively associated with OS and could contribute to the development of OS. In conclusion, the present study has identified several key genes that are potentially druggable genes or therapeutics targets in OS. Functional annotations revealed that the dysregulation of the ECM may contribute to OS development and, therefore, provided new insights to improve our understanding of the mechanisms underlying OS.

Targeting the VEGF Pathway in Osteosarcoma

“…Up to 70% of osteosarcoma have a loss-of-function mutation in the tumor suppressor gene encoding the Rb-associated protein [ 35 ]. Application of gene microarrays has shown an upregulation of genes affecting the extracellular matrix (ECM) that are involved in adhesion, cell and leukocyte migration suggesting a role of ECM dysregulation in OST tumorigenesis [ 36 ]. Furthermore, genomic sequencing of 66 pediatric and adult osteosarcoma using MSK-Impact, a large Next Generation sequencing (NGS) assay has identified at least one targetable molecular alteration in 14 pts (21%) including amplification of CDK4 and/or MDM2 (14% each) [ 37 ].…”

PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells

“…To address these issues and to identify TFs that are crucial for LSEC fating, CenTFinder combines gene co-expression analysis (WGCNA), TF binding motif enrichment analysis ( RcisTarget ), and differential gene expression analysis. Several studies have been published that combine microarray meta-analysis with gene co-expression methods 56 , 57 ; however, to date only a single study has combined this with TF binding motif enrichment as well 58 . Furthermore, the SCENIC workflow 39 , a well-established analysis tool for single-cell RNA-sequencing data, is in essence based on similar premises.…”

Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma

“…The rise of more modern and sensitive tools in molecular biology has allowed researchers to identify alterations in a plethora of genes related to different pathways in OS. Along with TP53 and RB1, other commonly affected genes include MYC, CDK4, and CDKN2 (cell cycle and apoptosis pathways); AURKB (mitosis pathways); ATRX, BRCA1 and BRCA2 (DNA damage repair); PIK3CA, ALK, NF1 and PTEN (PI3K-mTOR/RAS signaling pathways), NOTCH1-4 and AKT1 (Notch signaling pathway); DLG2 (Wnt signaling pathway); SATB2 (osteoblastic differentiation); VEGFA (receptor tyrosine kinase pathway); and genes related to the IGF (insulin-like growth factor) signaling pathways [7,[12][13][14][15][16][17][18][19][20]. In addition to altered genes, OS also exhibits abnormal gene regulation and epigenetic mechanisms.…”

“…Mechanistically, the effects of fasting regimes seem to be similar to those of CR, in that IGF-1 is reduced and AMPK is activated, inhibiting the PI3K/Akt-mTOR pathway. Additionally, due to the restriction of glucose, aerobic glycolysis, on which tumors rely for proliferation and immunosuppression, is also inhibited [17,101,103]. Moreover, the limitation of AA availability also impacts cancers, given that in general, they require large amounts of AA for cell proliferation and survival.…”