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)

Notch signaling plays crucial roles in many developmental pathways, with Notch mutations linked to several developmental disorders. Because many pediatric malignancies arise from dysregulated development, roles for Notch signaling in these cancers are to be expected. Evidence to support this is now emerging as the Notch pathway is being explored in more pediatric cancers. Not surprisingly, Notch appears to play diverse roles in different malignancies, effecting differentiation, metastasis, cancer "stem cells," and angiogenesis. As examples, although activating mutations of Notch1 are found in the majority of T-cell acute lymphoblastic leukemia (ALL) cases, Notch/HES1 signaling appears to play a tumor suppressor role in precursor B-cell ALL; although Notch/HES1 signaling appears to contribute to osteosarcoma metastasis, Notch signaling also promotes medulloblastoma "stem cell" survival and contributes to angiogenesis in neuroblastoma. Further understanding of the roles of Notch signaling in specific pediatric cancers will provide a rationale for Notch-based therapeutic strategies.
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PMID:Notch signaling in pediatric malignancies. 1892 60

The highly conserved NOTCH signaling pathway has many essential functions in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated NOTCH signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. An HES1 binding site is identified 400 bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers.
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PMID:Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. 2020 68

MicroRNAs (miRNAs) play important roles in the development, differentiation, and function of different cell types and in the pathogenesis of various human diseases. miRNAs are differentially expressed in normal and cancer cells. The investigation of miRNA expression between healthy subjects and patients with osteosarcoma is crucial for future clinical trials. We performed miRNA microarray analysis on 8 formalin-fixed, paraffin-embedded osteosarcoma tissue samples. We confirmed the results of the microarray analysis using reverse transcription polymerase chain reaction. miRNA profiling of osteosarcoma tissue samples showed that expression of 10 miRNAs had increased 10-fold compared with normal controls. Among the 10 miRNAs, 3 miRNAs (miR-199b-5p, miR-338-3p, and miR-891a) were confirmed to have been up-regulated by reverse transcription polymerase chain reaction. After transfection of 4 osteosarcoma cell lines with miR-199b-5p inhibitor, the expression of Notch pathway components in the transfected cell lines was changed. These results revealed that miR-199b-5p plays a role in Notch signaling in osteosarcoma. Recently, the inhibition of Notch and HES1 signaling has been suggested as a potential therapeutic strategy to prevent metastasis in human osteosarcoma. Taken together with our results, we suggest that miR-199b-5p inhibitor may also be a therapeutic option for osteosarcoma.
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PMID:MicroRNA-199b-5p is involved in the Notch signaling pathway in osteosarcoma. 2357 81

Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html).
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PMID:How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation. 2400 96

Doxorubicin plays a major role in the treatment of osteosarcoma disorders. The Notch signaling pathway exerts various biological functions, including cell proliferation, differentiation, and apoptosis. In the present study, we investigated the effects of different doses of doxorubicin on proliferation and apoptosis of osteosarcoma cells with or without Notch signaling. Results found that cellular viability was downregulated while caspase 3 activity and expression were promoted in osteosarcoma cells following treatment with various doses of doxorubicin for 24, 48, and 72 h, and the effects showed a dose- and time-dependent manner. Furthermore, it was found that various doses of doxorubicin activated the Notch signaling pathway, shown by the elevated expression of Notch target genes NOTCH1, HEY1, HES1, AND HES5. It was further proved that, after small interfering RNA (siRNA)-mediated knockdown of Notch, the effects of doxorubicin on the viability and apoptosis of osteosarcoma cells were significantly reduced. It was indicated that doxorubicin treatment reduced the proliferation and promoted the apoptosis of osteosarcoma cells, and this effect was mediated by the Notch signaling pathway.
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PMID:Doxorubicin Inhibits Proliferation of Osteosarcoma Cells Through Upregulation of the Notch Signaling Pathway. 2635 Dec 7