Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polo-like kinase (PLKs) family, consisting of five known members, are key regulators of important cell cycle processes, which include mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. The PLKs have been implicated in a variety of cancers, such as hepatocellular carcinoma (HCC), with PLK1 typically overexpressed and PLKs 2-5 often downregulated. Altered expression of the PLKs in malignancy is often correlated with aberrant promoter methylation. Epigenetic marks are dynamic and can be modified in response to external environmental stimuli. The aim of our study was to determine if oxidative stress, a common feature of solid tumours, would induce changes to the promoter methylation of the PLKs resulting in changes in expression. We examined the promoter methylation status via MSP and subsequent expression levels of the PLK family members under exposure to hypoxic conditions or reactive oxygen species (ROS). Interestingly, murine embryonic fibroblasts exposed to hypoxia and ROS displayed significant hypermethylation of Plk1 and Plk4 promoter regions post treatment. Corresponding proteins were also depleted by 40% after treatment. We also examined the HCC-derived cell lines HepG2 and Hep3B and found that for PLK1 and PLK4, the increase in hypermethylation was correlated with the presence of functional p53. In p53 wild-type cells, HepG2, both PLK1 and PLK4 were repressed with treatment, while in the p53 null cell line, Hep3B, PLK4 protein was elevated in the presence of hypoxia and ROS. This was also the case for ROS-treated, p53 null, osteosarcoma cells, Saos-2, where the PLK4 promoter became hypomethylated and protein levels were elevated. Our data supports a model in which the PLKs are susceptible to epigenetic changes induced by microenvironmental cues and these modifications may be p53-dependent. This has important implications in HCC and other cancers, where epigenetic alterations of the PLKs could contribute to tumourigenesis and disease progression.
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PMID:p53-Dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress. 2449 22

Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of aggressive phenotypes. Several studies report CIN and a tumorigenic and/or aggressive transformation in mitochondrial DNA (mtDNA)-depleted cells. Although several nuclear-encoded proteins are implicated in centrosome duplication and spindle organization, the involvement of mtDNA encoded proteins in centrosome amplification (CA) remains elusive. Here we show that disruption of mitochondrial function by depletion of mtDNA induces robust CA and mitotic aberrations in osteosarcoma cells. We found that overexpression of Aurora A, Polo-like kinase 4 (PLK4), and Cyclin E was associated with emergence of amplified centrosomes. Supernumerary centrosomes in rho0 (mtDNA-depleted) cells resulted in multipolar mitoses bearing "real" centrosomes with paired centrioles at the multiple poles. This abnormal phenotype was recapitulated by inhibition of respiratory complex I in parental cells, suggesting a role for electron transport chain (ETC) in maintaining numeral centrosomal homeostasis. Furthermore, rho0 cells displayed a decreased proliferative capacity owing to a G 2/M arrest. Downregulation of nuclear-encoded p53 in rho0 cells underscores the importance of mitochondrial and nuclear genome crosstalk and may perhaps underlie the observed mitotic aberrations. By contrast, repletion of wild-type mtDNA in rho0 cells (cybrid) demonstrated a much lesser extent of CA and spindle multipolarity, suggesting partial restoration of centrosomal homeostasis. Our study provides compelling evidence to implicate the role of mitochondria in regulation of centrosome duplication, spindle architecture, and spindle pole integrity.
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PMID:Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis. 2479 70

Dysregulated mitotic kinases have frequently been associated with cancer. Changes in their expression might result from diverse mechanisms including avoidance of the tight regulation exerted by miRNAs. Herein we show that miR-10b* is downregulated in osteosarcoma samples and demonstrate its correlation with PLK1, PLK4, BUB1, and BUBR1, which are strongly intercorrelated. The selection of miRNAs that coordinately target and regulate multiple members of cancer-related pathways are particularly advantageous to tumors. Thus, even though no associations with clinical parameters were found, our data place miR-10b* as a tumor suppressor that might contribute to guarantee genomic stability, deserving further functional confirmation.
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PMID:Downregulation of miR-10B* is correlated with altered expression of mitotic kinases in osteosarcoma. 2925 87

This study aimed to identify co-expressed differentially expressed genes (DEGs) in quiescence and senescence of osteosarcoma (OS) U2OS cells and investigate their biological functions. GSE94805 from Gene Expression Omnibus database was extracted, involving 12 samples of OS U2OS cells (4 quiescence, 4 senescence, and 4 control samples). After analysis of DEGs by limma package, VENN analysis was performed to identify co-expressed DEGs in quiescence and senescent. The Cytoscape software was used to construct an interactive network of co-expressed DEGs. Finally, box-plot was drawn for the co-expressed DEGs in sub-network. Besides, the relation literatures were selected in GenCLiP database for the co-expressed DEGs. Seven hundred and forty-three DEGs (255 up-regulated genes, 488 down-regulated genes) were obtained in quiescence and 2135 DEGs (1189 up-regulated genes, 946 down-regulated genes) in senescence. Through VENN analysis, 448 DEGs (131 up-regulated genes, 317 down-regulated genes) were co-expressed in quiescent and senescence. In the co-expressed DEGs network, 896 nodes (448 nodes in quiescent, 448 nodes in senescent) were obtained. Finally, 16 co-expressed DEGs were obtained in the sub-network analysis, in which Aurora kinase A (AURKA) and polo-like kinase (PLK4) had been reported in OS. AURKA and PLK4 might be the key genes in quiescence and senescence of OS U2OS cells.
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PMID:Differential expression of AURKA/PLK4 in quiescence and senescence of osteosarcoma U2OS cells. 3220 Jun 84

Osteosarcoma (OS) is a cancerous tumor in a bone. We aimed to identify the critical genes involved in OS progression, and then try to elucidate the molecular mechanisms of this disease. The microarray data of GSE32395 was used for the present study. We analyzed differentially expressed genes (DEGs) in OS cells compared with control group by Student's t-test. The significant enriched gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathways were analyzed for upregulated genes and downregulated genes, respectively. In addition, a protein-protein interaction (PPI) network was constructed. GO and KEGG enrichment analyses were conducted for genes in the PPI network. In total, 183 DEGs, including 100 upregulated DEGs and 83 downregulated DEGs were screened. The upregulated DEGs were significantly enriched in 2 KEGG pathways, such as "Glycosaminoglycan biosynthesis-chondroitin sulfate" and the downregulated DEGs were significantly enriched in 12 pathways, including "cell adhesion molecules," "pentose phosphate pathway" and "allograft rejection." GO enrichment analysis indicated that the upregulated DEGs were significantly involved in biological process, such as "multicellular organismal metabolic process" and "limb morphogenesis," while the downregulated DEGs were significantly enriched in biological process, such as "Positive regulation of pathway-restricted SMAD protein phosphorylation." The PPI network included 84 interactions and 51 nodes. The "glycosaminoglycan biosynthesis-chondroitin sulfate pathway," "microtubule motor activityfunction," and "regulation of mitosis process" were significantly enriched by genes in PPI network. In particular, CENPE, PRC1, TTK, and PLK4 had higher degrees in the PPI network. The interactions between TTK and PLK4 as well as CENPE and PRC1 may involve in the OS development. These 4 genes might be possible biomarkers for the treatment and diagnosis of OS.
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PMID:CENPE, PRC1, TTK, and PLK4 May Play Crucial Roles in the Osteosarcoma Progression. 3317 97