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1.
Medicine (Baltimore) ; 100(24): e26182, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128849

RESUMO

BACKGROUND: In recent years, a variety of long noncoding RNA (lncRNA) has been confirmed to be involved in the initiation and progression of osteosarcoma. Taurine-up regulated gene 1 (TUG1) plays an important role in the formation, invasion, and metastasis of osteosarcoma. Therefore, perhaps TUG1 is a potential biomarker for the prognosis of patients suffering from osteosarcoma. In this study, meta-analysis and bioinformatics were adopted to further explore the effects of TUG1 on the prognosis of patients with osteosarcoma and its potential molecular mechanism. METHODS: Embase, PubMed, Sinomed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and Vip Journal Integration Platform were searched from inception to May 2021. The relationship between TUG1 expression and survival outcome was estimated by hazard ratio (HRs) and 95% confidence interval (CIs). Meta-analysis was conducted on the Stata 16.0. The differential expression of TUG1 in osteosarcoma was analyzed by using UALCAN database, and the survival of TUG1 was analyzed as well. The target genes of TUG1 were predicted by RegRNA2.0 biology software, HMDD, targetscan and microTCDS, and TUG1-micoRNAs-mRNAs regulatory network was constructed. The predicted target genes obtained GeneOntology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal transduction pathway enrichment analysis using FunRich platform. RESULTS: The results of this meta-analysis would be submitted to peer-reviewed journals for publication. CONCLUSION: This study will provide evidence-based medical evidence for the relationship between TUG1 and the prognosis of osteosarcoma. Furthermore, bioinformatics analysis will provide ideas for the exploration on osteosarcoma mechanism. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results will be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/CW4BF.


Assuntos
Osteossarcoma/genética , Osteossarcoma/mortalidade , RNA Longo não Codificante/análise , Biomarcadores Tumorais/genética , Biologia Computacional , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Humanos , Masculino , Metanálise como Assunto , Prognóstico , Modelos de Riscos Proporcionais , Projetos de Pesquisa , Análise de Sobrevida , Revisões Sistemáticas como Assunto
2.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
3.
J Biol Regul Homeost Agents ; 35(3): 1021-1028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34157832

RESUMO

This study aimed to investigate the roles of hsa_circRNA_103801 in the progression of osteosarcoma (OS) cells. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the expression level of circRNA_103801 in OS cells. Cell count kit-8 and Transwell migration and invasion assays were employed to detect the proliferation, migration, and invasion abilities of OS cells. The effects of circRNA_103801 on the apoptosis of OS cells were identified by flow cytometry. The binding relationship between circRNA_103801 and miR-338-3p was verified by bioinformatics analysis. MiR-338-3p level in OS cell lines was detected by RT-qPCR. Additionally, Western blotting was utilized to detect the expression levels of HIF-1, Rap1, PI3K, and Akt in OS cells. The results showed that the expression level of circRNA_103801 was significantly up-regulated in OS patients' tissues. Inhibiting the expression level of circRNA_103801 could attenuate the proliferation, migration, and invasion abilities of OS cells. In addition, the down-regulated expression level of circRNA_103801 could induce cell apoptosis. The results of the luciferase reporter assay suggested that circRNA_103801 could be combined with miR-338-3p, and the RT-qPCR revealed that the miR-338-3p level in OS cells after knockdown of circRNA_103801 was elevated compared with the control group. The results of Western blotting suggested that the expression levels of HIF-1, Rap1, PI3K, and Akt were elevated in OS cells. In conclusion, the circRNA_103801-miR-3388-3p-HIF-1/Rap1/PI3K-Akt pathway could be a therapeutic target of OS.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , MicroRNAs/genética , Osteossarcoma/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular , Regulação para Cima
4.
Gen Physiol Biophys ; 40(3): 173-182, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34100374

RESUMO

This study aimed to identify more biomarkers associated with osteosarcoma progression via lncRNA-mRNA co-expression network. Dataset GSE99671 was downloaded from GEO database. The mRNAs and lncRNAs that were differentially expressed between tumor and normal samples were screened out. Functional enrichment analysis of differentially expressed mRNAs was carried out, followed by weighted gene correlation network analysis (WGCNA). Based on the lncRNAs and mRNAs, a lncRNA-mRNA co-expression network was constructed. Total 703 mRNAs and 7 lncRNAs were differentially expressed between tumor and normal tissues. The mRNAs were significantly enriched in functions associated with inflammatory response as well as autoimmune thyroid disease and ribosome pathways. WGCNA revealed that ME2 module had a high correlation with tumor, and ST3GAL4, UCK2, PSAT1 etc. had higher connectivity degrees in this module. lncRNA-mRNA co-expression network showed that 12 mRNAs, such as PEMT, COL10A1 and GSTA1, were synergistically expressed with lncRNA TTTY14. Inflammatory response and ribosome synthesis may play important role in osteosarcoma progression. lncRNA TTTY14 may affect the development of osteosarcoma by cooperative expression with PEMT, COL10A1, GSTA1, etc. ST3GAL4, UCK2, PSAT1 as well as TTTY14 may serve as key biomarkers in osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , RNA Longo não Codificante , Perfilação da Expressão Gênica , Humanos , Osteossarcoma/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética
5.
Aging (Albany NY) ; 13(10): 14258-14276, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34015762

RESUMO

Osteosarcoma is a malignant tumor with high mortality in children and adolescents. The mechanism of osteosarcoma metastasis is currently unclear. Abnormal expression of long non-coding RNA (lncRNA) plays an important role in tumor metastasis. We used bioinformatics to analyze the differences in gene expression between osteosarcoma in situ and osteosarcoma lung metastases. CCK-8 was used to detect the effect of lncRNA LOC100129620 on the proliferation of osteosarcoma cells. The effect of LOC100129620 on the invasion of osteosarcoma cells was assessed by Transwell assay. The regulatory effect of LOC100129620 on miR-335-3p was examined using RNA pull-down and luciferase reporter gene assays. The effect of LOC100129620 on the polarization of macrophages was detected by quantitative real-time fluorescent PCR. The results show that LOC100129620 can promote the proliferation and migration of osteosarcoma cells. LOC100129620 can promote the proliferation of osteosarcoma in vivo. LOC100129620 can bind to miR-335-3p and regulate its function. MiR-335-3p mediates the regulatory effects of LOC100129620 on CDK6. LOC100129620 promotes the formation of blood vessels and the polarization of macrophages. The LOC100129620/miR-335-3p/CDK6 signaling pathway promotes the metastasis of osteosarcoma by regulating the proliferation of osteosarcoma cells, angiogenesis, and macrophage polarization.


Assuntos
Polaridade Celular , Quinase 6 Dependente de Ciclina/genética , Progressão da Doença , Macrófagos/patologia , Neovascularização Patológica/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/metabolismo , Sequência de Bases , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Polaridade Celular/genética , Proliferação de Células/genética , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/secundário , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , RNA Longo não Codificante/genética , Regulação para Cima/genética
6.
Medicine (Baltimore) ; 100(20): e25952, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011074

RESUMO

BACKGROUND: Osteosarcoma represents the most common malignant bone tumor with high metastatic potential and inferior prognosis. RNA methylation (N6-methyladenosine [m6A]) is a prevalent RNA modification that epigenetically influences numerous biological processes including tumorigenesis. This study aims to determine that m6A regulators are significant biomarkers for osteosarcoma, and establish a prognostic model to predict the survival of patients. METHODS: In this study, we comprehensively analyzed the underlying associations between m6A regulators' mRNA expressions and metastasis as well as prognosis of osteosarcoma patients in the Cancer Genome Atlas. Multivariate Cox-regression analysis was used to screen regulators that were significantly associated with overall survival of osteosarcoma patients. Least absolute shrinkage and selection operator (LASSO) Cox-regression analysis was used for constructing m6A regulator-based osteosarcoma prognostic signature. RESULTS: Some of the regulators exhibited aberrant mRNA levels between osteosarcoma samples with and without metastasis. Multivariate Cox-regression analysis identified several regulators with potential prognostic significance. A risk score formula consisted of methyltransferase-like 3, YTH domains of Homo sapiens, and fat mass and obesity-associated protein was obtained through which patients could be prognostically stratified independently of potential confounding factors. The signature was also significantly associated with the metastatic potential of osteosarcoma. All the analyses could be well reproduced in another independent osteosarcoma cohort from the Gene Expression Omnibus. CONCLUSIONS: In conclusion, this study first revealed potential roles of m6A regulators in osteosarcoma metastasis and prognosis, which should be helpful for its clinical decision-making.


Assuntos
Biomarcadores Tumorais/genética , Osteossarcoma/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/análise , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metilação , Metiltransferases/análise , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Osteossarcoma/mortalidade , Osteossarcoma/secundário , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Processamento de RNA/análise , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA-Seq
7.
J Pharm Biomed Anal ; 201: 114088, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957363

RESUMO

This study aimed to compare the gene expression variation of clinical primary osteosarcoma (OS) and metastatic OS, identify expression profiles and signal pathways related to disease classification, and systematically evaluate the potential anticancer effect and molecular mechanism of ginsenoside Rh2 on OS. A raw dataset (GSE14359), which excluded GSM359137 and GSM359138, was downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) and principal component analysis (PCA) were obtained with limma. Pathways enrichment analysis was understood by GSEA app. Rh2-associated targets were harvested and mapped through PharmMapper and Cytoscape 3.4.0. The toxicity of Rh2 was determined using crystal staining and MTT assay on 143B and MG63 cell lines. The relative protein expression was confirmed through Western blot analysis. The mitochondrial membrane potential (△Ψm) was evaluated by JC-1 fluorescence staining. The cell mobility was measured via wound healing and transwell assays. A total of 752 genes were upregulated, while 161 genes were downregulated. GSEA and PCA displayed significant function enrichment and classification. Through PharmMapper and Cytoscape 3.4.0, Rh2 was found to target the mitogen activated protein kinase (MAPK) and PI3K signaling pathways, which are the key pathways in the metastasis of OS. Furthermore, Rh2 induced a concentration-dependent decrease in cell viability and early apoptosis associated with ΔΨm decline, while a non-lethal dose of Rh2 weakened the metastatic capability. Moreover, systematic evaluation showed that promoting the MAPK signaling pathway and inhibiting PI3K/Akt/mTOR were correlated with the anticancer effects of Rh2 on metastatic OS. In conclusion, transcriptome-derived approaches may be beneficial in diagnosing early metastases, and Rh2, a multi-targeting agent, shows promising application potential in suppressing metastatic OS in an MAPK- and PI3K/Akt/mTOR-dependent manner.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional , Ginsenosídeos , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Fosfatidilinositol 3-Quinases/genética
8.
Biomed Res Int ; 2021: 9917060, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997049

RESUMO

Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), a member of the 3-hydroxyacyl-CoA dehydrogenase family, were previously demonstrated to be involved in the tumorigenesis of various cancer types. This study is aimed at determining of the diagnostic and prognostic value of EHHADH in osteosarcoma (OS). The overexpression of EHHADH was found both in OS and also other sarcoma types, and according to the retrospective cohort study, the EHHADH level was related to the overall survival and disease-free survival of the OS patients. Furthermore, knockdown of EHHADH under the influence of EHHADH small interfering RNA significantly suppressed the proliferation ability of the tumor cells. Moreover, EHHADH overexpressed was found in human OS tissues. In summary, the progression of OS could be enhanced by EHHADH, which may be a potential diagnostic and prognostic biomarker for OS patients.


Assuntos
Osteossarcoma , Enzima Bifuncional do Peroxissomo , Linhagem Celular Tumoral , Humanos , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Enzima Bifuncional do Peroxissomo/genética , Enzima Bifuncional do Peroxissomo/metabolismo , Prognóstico , Mapas de Interação de Proteínas/genética , RNA Interferente Pequeno/genética , Estudos Retrospectivos
9.
Biomed Res Int ; 2021: 7463867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981772

RESUMO

Background: Chemoresistance is a major obstacle to the treatment of osteosarcoma patients. Circular RNA (circRNA) circPVT1 has been reported to be related to the doxorubicin (DXR) resistance in osteosarcoma. This study is designed to explore the role and mechanism of circPVT1 in the DXR resistance of osteosarcoma. Methods: circPVT1, microRNA-137 (miR-137), and TP53-regulated inhibitor of apoptosis 1 (TRIAP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels of ATP-binding cassette, subfamily C, member 1 (ABCC1), multidrug resistance-associated protein 1 (MRP-1), cleaved- (c-) caspase-3, B-cell lymphoma-2 (Bcl-2), and TRIAP1 were examined by a western blot assay. Cell viability, proliferation, and apoptosis were detected by cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays, severally. The binding relationship between miR-137 and circPVT1 or TRIAP1 was predicted by starbase 3.0 and then verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The biological role of circPVT1 in osteosarcoma tumor growth and drug resistance was examined by the xenograft tumor model in vivo. Results. circPVT1 and TRIAP1 were highly expressed, and miR-137 was decreased in DXR-resistant osteosarcoma tissues and cells. Moreover, circPVT1 knockdown could boost DXR sensitivity by inhibiting DXR-caused proliferation and DXR-induced apoptosis in DXR-resistant osteosarcoma cells in vitro. The mechanical analysis discovered that circPVT1 acted as a sponge of miR-137 to regulate TRIAP1 expression. circPVT1 silencing increased the drug sensitivity of osteosarcoma in vivo. Conclusion. circPVT1 boosted DXR resistance of osteosarcoma cells partly by regulating the miR-137/TRIAP1 axis, hinting a promising therapeutic target for the osteosarcoma treatment.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma , RNA Longo não Codificante , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia
10.
Cancer Sci ; 112(6): 2260-2271, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33837611

RESUMO

The lncRNA LINC01123 has been reported to act as an oncogene in many human cancers. Nevertheless, the function and underlying mechanism of LINC01123 in osteosarcoma (OS) remain unclear. This study aimed to explore the roles and mechanisms of LINC01123 in OS progression. In this study, the expression of LINC01123 was significantly upregulated in OS cell lines than in a human osteoblast cell line. Furthermore, in vitro and in vivo experiments confirmed that knockdown of LINC01123 suppressed cell progression. Mechanistically, LINC01123 acted as a competing endogenous RNA by sponging miR-516b-5p, thus, increasing Gli1 expression by directly targeting its 3'UTR. Taken together, LINC01123 enhances OS proliferation and metastasis via the miR-516b-5p/Gli1 axis. Therefore, LINC01123 may be a potential therapeutic target for OS treatment.


Assuntos
Neoplasias Ósseas/patologia , Proteínas Hedgehog/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/patologia , RNA Longo não Codificante/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Proteína GLI1 em Dedos de Zinco/genética
11.
Clin Lab ; 67(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33865271

RESUMO

BACKGROUND: The present study aimed to elucidate the clinical values of miR-337-3p, miR-484, miR-582, and miR-3677 in patients with osteosarcoma. METHODS: After extracting RNA from serum samples of healthy volunteers, OS patients, and periostitis patients, the real-time quantitative polymerase chain reaction (RT-qPCR) analysis was carried out. Afterwards, the receiver operating characteristic (ROC) assays were conducted in order to identify the area under the curves of certain microRNAs in OS. Finally, the log-rank survival analysis was used to analyze the five-year survival rate and disease-free survival rate of OS patients with aberrant microRNA expressions. RESULTS: From the results, miR-337-3p, miR-484, miR-582, and miR-3677 were remarkably decreased in OS cell lines, tumor tissues, and serum samples of OS patients. Furthermore, receiver operating characteristic (ROC) analysis verified that serum miR-337-3p, miR-484, miR-582, miR-711 and miR-3677 had favorable diagnostic values for identifying OS from periostitis patients with the area under the curves of 0.9434, 0.8760, 0.717,0 and 0.8705 and from healthy volunteers with the area under the curves 0.8218, 0.8358, 0.8008, and 0.7141, respectively. After surgery, serum miR-337-3p, miR-484, miR-582, and miR-3677 were dramatically increased. Meanwhile, lower expressions of miR-337-3p, miR-484, miR-582 and miR-3677 were strongly correlated with clinical stage and metastasis. Last but not the least, the log-rank survival analysis demonstrated that lower expressions of miR-337-3p, miR-484, miR-582, and miR-3677 were related to unfavorable prognosis in OS patients. CONCLUSIONS: Our study verified and illustrated the clinical values of miR-337-3p, miR-484, miR-582, and miR-3677 for the detection and prognosis of OS.


Assuntos
Neoplasias Ósseas , MicroRNAs/sangue , Osteossarcoma , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Prognóstico
12.
Biochem Biophys Res Commun ; 554: 214-221, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33813077

RESUMO

Osteosarcoma (OS) is the most common bone malignant tumor. However, the genetic basis of OS pathogenesis is still not understood, and occurrence of chemo-resistance is a major reason for the high morbidity of OS patients. Recently, chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) has been identified as a gene related to malignant tumor progression. Unfortunately, its effects on OS development and drug resistance are still not understood. In the study, we attempted to investigate the effects of CHD1L on tumorigenesis and chemoresistance in OS. We found that CHD1L expression was markedly up-regulated in OS samples, especially in cisplatin (cDDP)-resistant patients. We also showed that OS cells with CHD1L knockdown were more sensitive to cDDP treatment with lower IC50 values. In addition, we found that CHD1L deletion markedly reduced cell proliferation and induced apoptosis in OS cells with cDDP resistance. Moreover, the properties of cancer stem cells were highly suppressed in cDDP-resistant OS cells following CHD1L knockdown. Furthermore, multidrug resistance protein 1 (MDR-1) expression levels were dramatically decreased in OS cells with cDDP resistance when CHD1L was suppressed. Functional analysis indicated that CHD1L knockdown clearly restrained the activation of ERK1/2, protein kinase B (AKT) and NF-κB signaling pathways in cDDP-resistant OS cells. Consistently, animal experiments suggested that CHD1L suppression mitigated cDDP resistance in the generated in vivo xenografts. Collectively, CHD1L could modulate chemoresistance of OS cells to cDDP, and thus may be inspiring findings for overcoming drug resistance in OS.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Cisplatino/farmacologia , DNA Helicases/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Células-Tronco Neoplásicas/patologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Life Sci ; 277: 119501, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862108

RESUMO

AIMS: The present study evaluated the functions of Piperlongumine (PL) in osteosarcoma (OS) cell growth and metastasis both in vitro and in vivo. MAIN METHODS: MTT assay was conducted to test the cytotoxic effects of PL on the human osteoblasts line HFOB1.19 and the human normal chondrocyte line C28/I2T. FITC-Annexin V and propidium iodide (PI) were used to examine cell apoptosis. The migration, invasion and relative epithelial-mesenchymal transition were examined by Transwell assay and Western blotting. Reverse transcription-quantitative PCR (RT-qPCR) was performed to analyze the cytokine signaling 3 (SOCS3) mRNA expression. TargetScan database was used to predict the target of SOCS3. The binding association between miR-30d-5p and SOCS3 in U2OS and MG63 cells was evaluated by the dual-luciferase reporter assay. A xenograft model was constructed to evaluate the effect of PL on OS cell growth in vivo. KEY FINDINGS: The results revealed that PL inhibited the growth, migration, invasion, epithelial-mesenchymal transition, and promoted the apoptosis of OS cells dose-dependently. In addition, PL upregulated the protein levels of suppressor of SOCS3, while it inactivated the JAK2/STAT3 pathway, which was accompanied by a decreased level of microRNA (miR)-30d-5p. Furthermore, SOCS3was confirmed as a novel target of miR-30d-5p. Overexpression of miR-30d-5p not only led to decreased expression of SOCS3, but also dampened the antitumor effect of PL on OS. SIGNIFICANCE: The present data demonstrated that PL inhibited the progression of OS via downregulation of the SOCS3-mediated JAK2/STAT3 pathway by inhibiting miR-30d-5p.


Assuntos
Dioxolanos/farmacologia , MicroRNAs/genética , Osteossarcoma/metabolismo , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Dioxolanos/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Janus Quinase 2/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
14.
Biomed Res Int ; 2021: 5271291, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816613

RESUMO

Purpose: Osteosarcoma (Os) is the most frequent malignant tumor of the bone in the pediatric age group, and accumulating evidences show that lncRNAs play a key role in the development of Os. Thus, we investigated the role of RBM5-AS1 and its molecular mechanism. Methods: The expression of RBM5-AS1 in Os tissues and cell lines was detected by real-time polymerase chain reaction (QPCR). The effect of RBM5-AS1 on the proliferation of Os cells was detected using CCK8 assays and flow cytometry. The effect of RBM5-AS1 on the migration and invasion of Os cells was detected by transwell assays. And we performed QPCR and western blotting assays to investigate the relationship between RBM5-AS1 and RBM5. Finally, western blotting assays were performed to explore the mechanism of RBM5. Results: LncRNA RBM5-AS1 was overexpressed in the Os tissues and cell lines. And lncRNA RBM5-AS1 promoted Os cell proliferation, migration, and invasion in vitro and tumor growth in vivo. LncRNA RBM5-AS1 targets RBM5 in Os cells. Conclusion: To sum up, the results showed that lncRNA RBM5-AS1 promotes cell proliferation, migration, and invasion in Os.


Assuntos
Neoplasias Ósseas/metabolismo , Movimento Celular , Proliferação de Células , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética
15.
BMC Cancer ; 21(1): 355, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823834

RESUMO

BACKGROUND: The long non-coding (lnc) RNA activated by small nucleolar RNA host gene 16 (SNHG16), which has been reported to play a vital role in a number of different types of cancer, is a novel lncRNA. However, following an osteosarcoma (OS) study, the expression pattern, biological roles, clinical values and potential molecular mechanism of SNHG16 remain unclear. In the current study, we aimed to examine its expression and possible function in osteosarcoma (OS). METHOD: Cell proliferation was measured by colony formation assay and Cell Counting Kit-8 (CCK-8) in vitro, and xenograft transplantation assay in vivo. Meanwhile, we used transwell chambers to test cell migration and invasion was evaluated. Cell cycle and apoptosis was evaluated by flow cytometry assay. Immunoblotting and qPCR analysis was carried out to detect protein and gene expression, respectively. Luciferase reporter assay was used to predict the potential downstream genes. RESULTS: The present study demonstrated that SNHG16 is highly expressed in both the tissues of patients with OS, as well as OS cell lines, and its expression level was positively correlated with clinical stage and poor overall survival. Functional assays revealed that the depletion of SNHG16 inhibits OS growth, OS cell progression and promotes apoptosis both in vivo and in vitro. In addition, the present study revealed that microRNA-1285-3p expression levels can be decreased by SNHG16 acting as a 'sponge', and that this pathway takes part in OS tumor growth in vivo, and OS cell proliferation, invasion, migration and apoptosis in vitro. CONCLUSIONS: The results from the present study demonstrate the role of lncRNA SNHG16 in OS progression, which is SNHG16 might exert oncogenic role in osteosarcoma (OS) by acting as a ceRNA of miR-1285-3p, and it may become a novel target in OS therapy.


Assuntos
MicroRNAs/metabolismo , Osteossarcoma/genética , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Nus , Transfecção
16.
Biomed Res Int ; 2021: 7358153, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834074

RESUMO

The occurrence of osteosarcoma (OS) is associated with abnormal expression of many microRNAs (miRNAs). Exosomal miRNAs get much more attentions in intracellular communications. miR-1307 has been studied in many cancers, but its effects in OS have not been studied. We hypothesized that OS-derived exosomal miR-1307 regulates OS tumorigenesis. First, we found OS cell-derived exosomes (Exos) significantly promoted the proliferation, migration, and invasion of OS cells. Secondly, we found miR-1307 was highly expressed in OS cell-derived exosomes (OS-Exos), human OS tissues, and OS cell lines. Then, OS-Exos were extracted after OS cells were cultured and transfected with miR-1307 inhibitor, and the level of miR-1307 in OS-Exos was significantly reduced. When the level of miR-1307 in OS-Exos was significantly reduced, the effects of OS-Exos on migration, invasion, and proliferation of OS cells were also significantly weakened. Furthermore, using TargetScan, miRDB, and mirDIP databases, we identified that AGAP1 was a target gene of miR-1307. Overexpression of miR-1307 could inhibit the expression of AGAP1 gene. We also found AGAP1 was lower expressed in human OS tissues and OS cell lines. Luciferase gene indicated that miR-1307 directly bound the 3'-UTR of AGAP1. miR-1307 was negatively correlated with AGAP1 in clinical study. miR-1307 could significantly promote the proliferation, migration, and invasion of OS cells. In addition, upregulation of AGAP1 could significantly inhibit the role of miR-1307 in OS. In conclusion, our study suggests that OS cell-derived exosomal miR-1307 promotes the proliferation, migration, and invasion of OS cells via targeting AGAP1, and miR-1307-AGAP1 axis may play an important role in the future treatment of OS.


Assuntos
Exossomos/genética , Proteínas Ativadoras de GTPase/metabolismo , MicroRNAs/genética , Osteossarcoma/genética , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Zhonghua Zhong Liu Za Zhi ; 43(4): 457-465, 2021 Apr 23.
Artigo em Chinês | MEDLINE | ID: mdl-33902208

RESUMO

Objective: To investigate the effect of hsa_circ_0006948 (circ_0006948) on the proliferation, migration and invasion of osteosarcoma cells and the underlying mechanism. Methods: A total of 120 osteosarcoma tissues and 40 adjacent normal tissue samples were collected from patients admitted to the First People's Hospital of Shangqiu City from 2009 to 2015. Microarray analysis was performed to detect the differential expressions of circRNA in Saos-2 cell. The mRNA expressions of circ_0006948, microRNA (miR)-490-3p and autophagy-related protein 7 (ATG7) in osteosarcoma cells, NHOst cells, osteosarcoma tissues and adjacent tissues were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Cell clone formation assay was used to detect cell proliferation ability, Transwell assay was used to detect cell invasion ability, and cell scratch assay was used to detect cell migration ability. The interactions between circ_0006948 and miR-490-3p, miR-490-3p and ATG7 were detected by dual luciferase reporter gene assay. The correlation between miR-490-3p and ATG7 was analyzed by TargetScan database, and the expression levels of Bcl-2 and Bax proteins in cells were detected by western blot. Results: The mRNA expression levels of circ_0006948, miR-490-3p and ATG7 in SAOS-2 cells were significantly different from NHOst cells (P<0.01). The mRNA expression levels of circ_0006948, miR-490-3p and ATG7 in osteosarcoma tissues were significantly different from adjacent tissues (P<0.01). The numbers of cell clone, migration and mobility in circ_0006948-siRNA group were (32.78±1.76), (37.58±1.82) and (36.93±1.45)%, respectively, lower than (65.72±1.45), (78.63±1.93) and (65.32±1.74)% in the siRNA NC group (all P<0.01). The numbers of cell clone, migration and mobility in the miR-490-3p mimics group were (20.08±1.54), (30.24±1.78) and (21.15±1.68)%, respectively, lower than (60.36±1.83), (76.93±1.64) and (40.56±1.27)% in the mimics NC group (all P<0.01). The numbers of cell clone, migration and mobility in the miR-490-3p inhibitor+ siRNA NC group were (90.34±1.72), (120.89±2.34) and (70.83±1.93)%, respectively, higher than (61.27±1.73), (75.82±1.82) and (42.38±1.74)% in the inhibitor NC+ siRNA NC group (P<0.01). The numbers of cell clone, migration and mobility in the circ_0006948 siRNA+ miR-490-3p inhibitor group were (58.74±1.98), (73.46±1.04) and (40.35±1.72)%, respectively, lower than (90.34±1.72), (120.89±2.34) and (70.83±1.93)% in the miR-490-3p inhibitor+ siRNA NC group (P<0.01). The numbers of cell clone, migration and mobility in the ATG7 siRNA group were (20.56±1.87), (40.36±1.76) and (20.96±1.73)%, lower than (65.46±1.74), (90.87±2.32) and (40.87±2.03)% in the siRNA NC group (P<0.01). The absorbance of miR-490-3p mimics+ pcDNA-ATG7 group was 0.54±0.11, higher than (0.36±0.08) of miR-490-3p mimics group (P<0.05). The expression levels of Bax and Bcl-2 protein in Saos-2 cells of miR-490-3p mimics group were significantly different from mimics NC group (P<0.01). The protein expression levels of Bax and Bcl-2 in Saos-2 cells of miR-490-3p mimics + pcDNA-ATG7 group were significantly different from miR-490-3p mimics group (P<0.01). Conclusion: Circ_0006948 regulates ATG7 expression through miR-490-3p, therefore regulates the proliferation, migration and invasion of osteosarcoma cells.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Proteína 7 Relacionada à Autofagia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , MicroRNAs/genética , Osteossarcoma/genética
18.
Medicine (Baltimore) ; 100(14): e24118, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832059

RESUMO

ABSTRACT: Genetic alterations are vital to the progression of osteosarcoma carcinoma. The present study investigated a panel of gene signatures that could evaluate prognosis in osteosarcoma based on data from the Therapeutically Applicable Research To Generate Effective Treatments initiative. Osteosarcoma messenger RNA (mRNA) profiles and clinical data were downloaded from the therapeutically applicable research to generate effective treatments database. Patients with osteosarcoma were divided into two groups based on findings at diagnosis: with and without metastasis. Differentially expressed mRNAs were compared and analyzed between groups. Univariate and multivariate Cox regression analyses identified a set of eight mRNAs with the ability to classify patients into high-risk and low-risk groups with significantly different overall survival times. Further analysis indicated that the eight-mRNA signature was an independent prognostic factor after adjusting for other clinical factors. Receiver operating characteristic curve analysis demonstrated a good performance of the eight-mRNA signature. Further, the biological processes and signaling pathways of the eight-mRNA signature were reviewed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes resources. Finally, the results of the TCGA analysis were verified by other cohorts from Gene Expression Omnibus database. The identification of an eight-mRNA signature not only provides a prognostic biomarker of osteosarcoma but also offers the potential of novel therapeutic targets for its treatment.


Assuntos
Neoplasias Ósseas/genética , Osteossarcoma/genética , RNA Mensageiro/metabolismo , Adolescente , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/mortalidade , Criança , Bases de Dados Factuais , Feminino , Humanos , Masculino , Osteossarcoma/mortalidade , Curva ROC , Análise de Sequência de RNA , Transcriptoma
19.
Braz J Med Biol Res ; 54(6): e10474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886809

RESUMO

Osteosarcoma is a highly malignant tumor that occurs in the bone. Previous studies have shown that multiple microRNAs (miRNAs) regulate the development of osteosarcoma. This study aimed to explore the role of miR-629-5p and its target gene, caveolin 1 (CAV1), in osteosarcoma development. To analyze the expression of miR-629-5p and CAV1 mRNA in osteosarcoma tissues and cell lines, qRT-PCR analysis was performed. Dual-luciferase reporter experiments were subsequently performed to validate the relationship between CAV1 and miR-629-5p. CCK8 assay was used to measure osteosarcoma cell proliferation, and wound-healing assay was performed to study their migratory phenotype. Our findings revealed that miR-629-5p was overexpressed in osteosarcoma tissues and cells, and thereby enhanced cell proliferation and migration. Further, we validated that miR-629-5p targets CAV1 mRNA directly. CAV1 expression, which was negatively correlated with miR-629-5p expression, was found to be downregulated in osteosarcoma tissue samples. Moreover, our data showed that an increase in CAV1 level led to a decline in osteosarcoma cell proliferation and migration, which could be rescued by miR-629-5p upregulation. Overall, our study confirmed that miR-629-5p promoted osteosarcoma proliferation and migration by directly inhibiting CAV1.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Neoplasias Ósseas/genética , Caveolina 1/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Osteossarcoma/genética
20.
Biochem Biophys Res Commun ; 554: 25-32, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33774276

RESUMO

Osteosarcoma, a highly aggressive malignant tumor of the bone, usually occurs in children and young adults. However, although the considerable achievement in the clinical treatment of osteosarcoma recent years, the overall survival of osteosarcoma patients has not been obviously improved. Cancer cells preferentially use glycolysis instead of oxidative phosphorylation to meet their increased energetic and biosynthetic demands, a phenomenon known as the Warburg effect. Glycolysis is a driving factor in multiple cancers and is emerging as a new cancer target treatment. In the present study, we established a model to screen for glycolysis-associated genes in osteosarcoma. This risk score of the model were correlated with clinical characteristics osteosarcoma patients. Besides, a functional assay identified that STC2 enhanced the glycolysis of osteosarcoma cells. Modulation of STC2 changes glucose consumption and lactate production as well as GLUT1 expression in osteosarcoma. Furthermore, we identified that change in the expression levels of STC2 affected the proliferation, invasion, and migration of osteosarcoma cells. Our findings showed STC2 as a new tumor-promoting factor of osteosarcoma cells through enhancing glycolysis.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Glucose/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácido Láctico/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Biologia Computacional , Bases de Dados Genéticas , Glicólise , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteossarcoma/genética , Prognóstico , Taxa de Sobrevida
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