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1.
Gene ; 721: 144093, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473323

RESUMO

Previous studies have determined that long non-coding RNA (lncRNA) Fer-1-like protein 4 (FER1L4) is suppressed in osteosarcoma (OS) and inhibits the tumorigenesis in a variety of cancer. However, the precise biological of FER1L4 in OS has not been cleared. The aim of this study is to investigate the roles and potential mechanisms of FER1L4 in apoptosis and epithelial-mesenchymal transition (EMT) in OS. In the present study, the levels of FER1L4 were decreased significantly in OS tissues and cell lines compared with non-tumorous tissues or hFOB1.19. Knockdown of FER1L4 in OS cells decreased the apoptosis rate, but increased the OS cell proliferation, upregulated the expression levels of CD133 and Nanog, as well as promoted Twist1 expression, increased the N-cadherin and Vimentin expression. In turn, the opposite trends were observed upon overexpression of FER1L4. In addition, the expression of PI3K, p-AKT (Ser470) and p-AKT (Thr308) was upregulated by siFER1L4, while decreased upon overexpression of FER1L4. MicroRNA (miRNA) -18a-5p, an osteosarcoma-promoting miRNA which was suggested a target of FER1L4 in osteosarcoma, was identified to be a functional target of FER1L4 on the regulating of cell apoptosis and EMT, presently. The effects of FER1L4 overexpression on the markers of cell apoptosis, proliferation, EMT, and stemness and PI3K/AKT signaling were all reversed by miR-18a-5p upregulation. Furthermore, the suppressor of cytokine signaling 5 (SOCS5) was confirmed a target gene of miR-18a-5p by luciferase gene reporter assay and SOCS5 suppression by miR-18a-5p attenuated the effects of FER1L4 overexpression on the OS cells apoptosis and the expressed levels of PI3K, AKT, Twist1, N-cadherin and Vimentin. In conclusion, our data indicated thatthe overexpression of FER1L4 promoted apoptosis and inhibited the EMT markers expression and PI3K/AKT signaling pathway activation in OS cells via downregulating miR-18a-5p to promote SOCS5.


Assuntos
Apoptose , Neoplasias Ósseas/metabolismo , Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Proteínas Supressoras da Sinalização de Citocina/genética
2.
Life Sci ; 234: 116771, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421084

RESUMO

AIMS: We aimed to elucidate the effects and mechanisms of MAT1 in the progression of osteosarcoma, especially for its lung metastasis. MAIN METHODS: CCK-8 and flow cytometry assays were carried out to detect the proliferation and apoptosis of osteosarcoma cells. Wound healing and transwell assays were used to determine cell migration and invasion abilities. Real time quantitative PCR (RT-PCR) and western blot technologies were applied to detect the expression levels of RNA and protein, respectively. KEY FINDS: The results showed that both the mRNA and protein expression levels of MAT1 were elevated in osteosarcoma tissues with lung metastasis and metastatic lung tissues, particularly in the metastatic lung tissues, as compared to the osteosarcoma tissues without lung metastasis. High expression level of MAT1 in osteosarcoma patients showed a negative association with the overall survival. In addition, upregulation of MAT1 induced significant increases in cell growth, migration and invasion and an obvious inhibition in cell apoptosis in osteosarcoma MG63 and 143B cells, as well as elevated AKT1 expression level. Moreover, knockdown of AKT1 obviously impaired MAT1-mediated promotions in cell migration and invasion in vitro, as well as repressed tumor growth and reduced the number of metastatic lung tumors in xenografted nude mice. SIGNIFICANCE: This study reveals that high expression of MAT1 closely related to the poor prognosis and malignant clinical process of osteosarcoma patients. MAT1 serves as a promoter in the lung metastasis of osteosarcoma through increasing AKT1 expression. Our study may provide a potent therapeutic target for the lung metastasis of osteosarcoma.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Neoplasias Ósseas/patologia , Proteínas de Transporte/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/genética , Regulação para Cima , Adulto Jovem
3.
Anticancer Res ; 39(8): 4079-4084, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366491

RESUMO

BACKGROUND/AIM: Recurrent osteosarcoma is a recalcitrant disease; therefore, an improved strategy is urgently needed to provide therapy. In order to develop a novel strategy for this disease, our lab has developed a patient-derived orthotopic xenograft (PDOX) mouse model for osteosarcoma. The combination of sorafenib (SFN) and palbociclib (PAL) was shown to be effective of hepatocellular carcinoma. However, whether this combination is efficacious on osteosarcoma has not been reported. The aim of this study was to determine the efficacy of the SFN and PAL combination on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into five treatment groups: untreated-control, CDDP, SFN, PAL and the combination of SFN and PAL. RESULTS: Of these agents, the SFN-PAL combination significantly regressed tumor growth, and enhanced tumor necrosis with degenerative changes in the osteosarcoma PDOX. CONCLUSION: The SFN-PAL combination is an effective treatment strategy for osteosarcoma and therefore holds promise for clinical efficacy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Osteossarcoma/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Humanos , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Life Sci ; 233: 116757, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419446

RESUMO

AIMS: Previous studies have demonstrated that long non-coding RNAs (lncRNAs) were involved in tumorigenesis in various human neoplasms, including osteosarcoma (OS). However, the expression and specific role of lncRNA linc00460 in OS remain unknown. MATERIALS AND METHODS: Bioinformatics analysis, Quantitative real-time polymerase chain reaction (qRT-PCR), CCK-8 assay, Colony formation assay, Wound healing assay, Transwell assay, Dual luciferase reporter assay, RNA immunoprecipitation and Western blot were utilized to analyze or detect survival, gene expression, cell proliferation, cell migration, cell invasion and interest protein levels, respectively. KEY FINDINGS: In this study, we found high linc00460 expression predicted poor prognosis of pan-cancer patients. Linc00460 was up-regulated in OS tissues and cells. High linc00460 expression was positively correlated with distant metastasis and poor overall survival of OS patients. Knockdown of linc00460 suppressed OS cells proliferation and metastasis in vitro. In addition, an inverse correlation between linc00460/miR-1224-5p and miR-1224-5p/FADS1 was observed in OS. Mechanistically, linc00460 functioned as a competitively endogenous RNA (ceRNA) to up-regulate FADS1 expression via sponging miR-1224-5p in OS, thereby promoting OS progression. SIGNIFICANCE: In conclusion, this study recognized linc00460 as a new oncogenic lncRNA in OS and suggests that the linc00460/miR-1224-5p/FADS1 axis might be a potential therapeutic target for OS.


Assuntos
Neoplasias Ósseas/patologia , Ácidos Graxos Dessaturases/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , Adulto , Apoptose , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/cirurgia , Movimento Celular , Proliferação de Células , Progressão da Doença , Ácidos Graxos Dessaturases/genética , Feminino , Humanos , Masculino , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/cirurgia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
5.
DNA Cell Biol ; 38(9): 996-1004, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31393166

RESUMO

Osteosarcoma (OS), a highly aggressive bone tumor, mainly occurs in young patients and always presents abnormalities in molecular biology, such as microRNAs (miRNAs). However, the characteristic and underlying mechanism of miR-671-5p in OS are still unclear. In this study, we certify that miR-671-5p is remarkably downregulated in OS tissues and cells. Overexpressed miR-671-5p can suppress OS cell proliferation in vivo and in vitro, by the way of arresting cell-cycle progression. The overexpression of cyclin D1 (CCND1) and CDC34 promotes cell proliferation and cell-cycle promotion, whose functions are contrary to miR-671-5p. miR-671-5p directly binds to CCND1 and CDC34, which are thought as the key factors in regulating cell cycle. Taken together, our results suggest that by targeting CCND1 and CDC34, miR-671-5p plays a tumor suppressor in OS to inhibit the development of OS, implicating it as a novel target for therapeutic intervention in OS.


Assuntos
Ciclo Celular , Proliferação de Células , MicroRNAs/genética , Osteossarcoma/genética , Animais , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Osteossarcoma/patologia , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
6.
Yonsei Med J ; 60(9): 832-841, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31433581

RESUMO

PURPOSE: Epirubicin is one of the most effective drugs against osteosarcoma. miR-1301 is involved in the occurrence and development of osteosarcoma. Whether miR-1301 is responsible for the chemosensitivity of osteosarcoma cells to epirubicin remains largely unknown. MATERIALS AND METHODS: U2OS and SAOS-2 cells were treated with various concentrations of epirubicin. Flow cytometry was employed to evaluate cell apoptotic rate. Cell proliferation was measured by Cell Counting Kit-8 assay. Western blot and quantitative real-time polymerase chain reaction were utilized to detect the expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 assaciated X protein (Bax), cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerases (PARP1), TP53-regulated inhibitor of apoptosis 1 (TRIAP1), and microRNA-1301 (miR-1301). The relationship between miR-1301 and TRIAP1 was determined by luciferase reporter assay. RESULTS: Epirubicin inhibited proliferation in a dose-dependent manner, induced apoptosis, decreased the expression of Bcl-2, and increased the expressions of Bax, cleaved-caspase-3, and cleaved-PARP1 in osteosarcoma cells. miR-1301 was downregulated in U2OS and SAOS-2 cells. Importantly, epirubicin significantly increased the levels of miR-1301. Overexpression of miR-1301 suppressed proliferation and promoted apoptosis. Interestingly, those effects were enhanced by epirubicin. In contrast, miR-1301 depletion attenuated the epirubicin-mediated anti-osteosarcoma effect. miR-1301 negatively regulated the expression of TRIAP1 in U2OS and SAOS-2 cells. Furthermore, epirubicin inhibited the mRNA and protein levels of TRIAP1 by upregulating miR-1301 levels. Epirubicin suppressed cell proliferation by downregulating TRIAP1. CONCLUSION: miR-1301 was implicated in the chemosensitivity of osteosarcoma to epirubicin by modulating TRIAP1.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Epirubicina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Caspase 3/biossíntese , Linhagem Celular Tumoral , Regulação para Baixo , Epirubicina/farmacologia , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
7.
Int J Oncol ; 55(1): 167-178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180533

RESUMO

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor­3 (DR3) and decoy receptor­3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF­A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re­expression of tumor suppressor genes in cancer cells, but also exert anti­angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF­A interference.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Hidralazina/farmacologia , Osteossarcoma/tratamento farmacológico , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Ácido Valproico/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Transcrição Genética/efeitos dos fármacos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
8.
Gene ; 710: 246-257, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31176732

RESUMO

Osteosarcoma is the most common primary bone tumor during childhood and adolescence. Several reports have presented data on serum biomarkers for osteosarcoma, but few reports have analyzed circulating microRNAs (miRNAs). In this study, we used next generation miRNA sequencing to examine miRNAs isolated from microvesicle-depleted extracellular vesicles (EVs) derived from six different human osteosarcoma or osteoblastic cell lines with different degrees of metastatic potential (i.e., SAOS2, MG63, HOS, 143B, U2OS and hFOB1.19). EVs from each cell line contain on average ~300 miRNAs, and ~70 of these miRNAs are present at very high levels (i.e., >1000 reads per million). The most prominent miRNAs are miR-21-5p, miR-143-3p, miR-148a-3p and 181a-5p, which are enriched between 3 and 100 fold and relatively abundant in EVs derived from metastatic SAOS2 cells compared to non-metastatic MG63 cells. Gene ontology analysis of predicted targets reveals that miRNAs present in EVs may regulate the metastatic potential of osteosarcoma cell lines by potentially inhibiting a network of genes (e.g., MAPK1, NRAS, FRS2, PRCKE, BCL2 and QKI) involved in apoptosis and/or cell adhesion. Our data indicate that osteosarcoma cell lines may selectively package miRNAs as molecular cargo of EVs that could function as paracrine agents to modulate the tumor micro-environment.


Assuntos
Neoplasias Ósseas/genética , Vesículas Extracelulares/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , MicroRNAs/genética , Osteossarcoma/genética , Apoptose , Adesão Celular , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Metástase Neoplásica , Análise de Sequência de RNA/métodos
9.
Bioengineered ; 10(1): 133-141, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31055998

RESUMO

OBJECTIVE: S100A9 is a calcium- and zinc-binding molecule of S100 family. The aim of the study was to evaluate the role of S100A9 in osteosarcoma (OS) and its value as a diagnostic and therapeutic target in OS. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and microdissection-based mRNA analysis were used to detect S100A9 mRNA and protein expression in OS and normal bone tissues and its potential as a diagnostic marker in OS. In vitro experiments with RNA interference were performed to evaluate the functional role of S100A9 and its potential as a therapeutic target in OS. RESULTS: S100A9 mRNA levels were significantly higher in OS tissues than that of in normal bone tissues. Receiver operating characteristic curves showed that S100A9 could be a useful diagnostic marker in OS. In vitro data showed that inhibition of S100A9 decreased the proliferation and invasiveness of OS cells, and these findings were supported by microarray data. CONCLUSIONS: Assessment of S100A9 mRNA expression is a promising tool for the diagnosis of OS, and S100A9 may be a promising therapeutic target in OS.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/diagnóstico , Calgranulina B/genética , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/diagnóstico , RNA Mensageiro/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Calgranulina B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Invasividade Neoplásica , Proteínas de Neoplasias , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Curva ROC , Transdução de Sinais
10.
Int J Oncol ; 54(6): 1921-1932, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081054

RESUMO

Osteosarcoma (OS) is a common primary malignancy in adolescents and children. MicroRNAs (miRNAs or miRs) can regulate the progression of OS. Herein, we explored the target genes and effects of miR­9 in OS. Cell growth, colony formation and cell cycle were respectively examined using a cell counting kit­8 (CCK­8), crystal violet staining and flow cytometry. The target gene of miR­9 was predicted according to the MicroRNA.org website. Luciferase activity was examined using a dual luciferase reporter gene assay kit. The corresponding factors levels were analyzed by carrying out reverse transcription­quantitative PCR (RT­qPCR) and western blot analysis. A mouse model of OS was also established and the volume and weight of the tumors of the mice with OS were measured. The levels of p16 in the mice with OS were detected by immunohistochemistry (IHC). The data revealed a high expression of miR­9 and a low expression of p16 in the OS tissue. p16 was found to be the target gene for miR­9 in OS. miR­9 depletion decreased the proliferation and colony formation of Saos­2 cells by arresting the cells at the G1 phase, accompanied by the downregulation of cyclin A, cyclin D1 and c­Myc expression levels. Moreover, miR­9 depletion inhibited the phosphorylation of p38, c­Jun N­terminal kinase (JNK) and extracellular signal­regulated kinase (ERK). In vivo, miR­9 depletion decreased the tumor volume and weight and increased p16 expression in the mouse tumor tissues. Nevertheless, p16 silencing reversed the suppressive effects of miR­9 inhibitors on OS cells. On the whole, the findings of this study substantiate that miR­9 depletion suppresses cell proliferation by targeting p16 in OS and by mediating the activation of the ERK/p38/JNK pathway.


Assuntos
Neoplasias Ósseas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , MicroRNAs/genética , Osteossarcoma/patologia , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Osteossarcoma/genética , Osteossarcoma/metabolismo , Prognóstico , Análise de Sobrevida
11.
Cancer Biother Radiopharm ; 34(4): 258-263, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31070482

RESUMO

Background: Downregulation of LncRNA LINC-PINT has been observed in different types of cancer cells, indicating its role as a tumor suppressor. Materials and Methods: Expression of LINC-PINT and miRNA-21 in tumor tissues and adjacent healthy tissues of 56 patients with osteosarcoma was detected by real-time quantitative PCR. Correlations between expression levels of LncRNA LINC-PINT and miRNA-21 were analyzed by Pearson's correlation coefficient. Results: In this study, we found that LncRNA LINC-PINT was inhibited, whereas miRNA-21 was promoted in tumor tissues than in adjacent healthy tissues of patients with osteosarcoma. Expression levels of LncRNA LINC-PINT were affected by both tumor size and tumor metastasis. LncRNA LINC-PINT and miRNA-21 were significantly and reversely correlated in both tumor cells and adjacent healthy tissues. LncRNA LINC-PINT overexpression led to downregulated miRNA-21 expression in cancer cells, whereas miRNA-21 overexpression did not significantly affect LINC-PINT expression. Overexpression of LncRNA LINC-PINT inhibited whereas miRNA-21 overexpression promoted cancer cell proliferation, migration, and invasion. In addition, miRNA-21 overexpression partially rescued the inhibited cell proliferation, migration, and invasion mediated by LncRNA LINC-PINT overexpression. Conclusion: Therefore, LncRNA LINC-PINT may inhibit cancer cell proliferation, invasion, and migration in osteosarcoma by downregulating miRNA-21.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/genética , RNA Longo não Codificante/metabolismo , Adolescente , Adulto , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Carga Tumoral/genética , Regulação para Cima , Adulto Jovem
12.
Cancer Biother Radiopharm ; 34(4): 264-270, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31070483

RESUMO

Purpose: Many studies have revealed that microRNAs (miRNAs) play crucial roles in cancer development and progression. miRNA-217 (miR-217) has been implicated in various cancers. However, the role of miR-217 in osteosarcoma (OS) remains unclear. In this study, the authors examined the role of miR-217 in development of OS. Materials and Methods: Using quantitative real-time PCR, they assessed expression levels of miR-217 in cultured cells and patient samples and examined the proliferation, migration, and invasion of cultured cells by MTT cell proliferation assays, cell scratch test, and cell transwell test. The proliferation, migration, and invasion were examined for MG63 and U2OS transfected by miR-217. Silent information regulator 2 homolog 1 (SIRT1) overexpression plasmid was designed. Results: Expression of miR-217 was downregulated in samples of OS tissue and cultured cells. Proliferation, migration, and invasion were inhibited by ectopic overexpression of miR-217. SIRT1 was identified as targets of miR-217. Expression levels of SIRT1 were inhibited by miR-217 expression in cultured cells, and the expression levels of miR-217 and SIRT1 were inversely correlated in patients with OS. Conclusion: MiR-217 acts as a tumor suppressor in the development of OS. The tumor-suppressive function of miR-217 in OS suggests inhibition of SIRT1.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Osteossarcoma/genética , Sirtuína 1/genética , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Regulação para Cima
13.
Hum Cell ; 32(3): 390-396, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079326

RESUMO

Dysregulation of microRNAs (miRNAs) is frequently found in the tumorigenesis of osteosarcoma (OS). miR-376a was found to play tumor suppressive roles in human cancers. However, the role of miR-376a in OS remains unclear. The expression of miR-376a was analyzed by quantitative real-time PCR (qRT-PCR) in OS cell lines. Cell proliferation assay, cell invasion assay, and cell apoptosis assay were performed to detect the biological function of miR-376a after synthetic miRNA transfection. The target of miR-376a was predicted by TargetScan and miRDB, and further validated by luciferase activity reporter assay and western blot. miR-376a expression was revealed to be decreased in OS cell lines. In vitro experiments showed that overexpression of miR-376a inhibits OS cell proliferation and invasion but promotes apoptosis. Luciferase activity reporter assay and western blot assay showed F-box protein 11 (FBXO11) was a direct target of miR-376a. Furthermore, FBXO11 mediated the role of miR-376a on the proliferation, invasion, and apoptosis of OS cells. Collectively, these results revealed miR-376a functions as a tumor suppressor by targeting FBXO11 in OS. It may be developed as a therapeutic target for OS patients.


Assuntos
Proliferação de Células/genética , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Apoptose/genética , Células Cultivadas , Humanos , MicroRNAs/fisiologia , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Osteossarcoma/terapia
14.
Zhonghua Zhong Liu Za Zhi ; 41(5): 338-345, 2019 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-31137166

RESUMO

Objective: To detect the effect and regulatory mechanism of human ether à go-go related gene 1 (Herg 1) knockdown on the proliferation and invasion of osteosarcoma (OS). Methods: We constructed a recombinant adenovirus vector (Ad5-Herg1-shRNA) expressing short hair RNA (shRNA) against Herg1 and tested the knockdown efficiency. Then, the effects of Herg 1 knockdown on the proliferation, growth and invasion of osteosarcoma were measured by using cell counting kit-8 (CCK-8), wound healing assay, Transwell assay and xenograft model of nude mice, respectively. Tandem affinity purification, mass spectrometry and dual luciferase reporter assay were used to find out the molecules interacted with Herg1. Western blot was used to detect the expressions of large tumor suppressor gene (LATS1), p-LATS1, Yes-associated protein (YAP) and p-YAP in cells after infection of Ad5-Herg1-shRNA. Results: Compared to Ad5-control-shRNA, Ad5-Herg1-shRNA dramatically inhibited the expression of Herg1 in OS cells. The result of CCK8 array demonstrated that 143B cell vitalities of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (65.47±3.90)% and (79.90±1.52)%, significantly lower than (100.00±6.14)% of Ad5-control-shRNA group. Meanwhile, U2OS cell vitality of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (69.69±1.36)% and (76.72±2.75)%, significantly lower than (100.00±3.01)% of Ad5-control-shRNA group (all P<0.001). The results of wound healing array showed that 143B cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (33.03±2.88)% and (36.47±4.16)%, significantly lower than (97.78±2.28)% of Ad5-control-shRNA group. Meanwhile, U2OS cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were (68.07±0.90)% and (73.97±1.25)%, significantly lower than (96.50±1.12)% of Ad5-control-shRNA group (all P<0.001). The results of Transwell showed that 143B cell invasion numbers of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were 36.50±12.15 and 44.83±7.62, significantly lower than 195.33±19.68 of Ad5-control-shRNA group. Meanwhile, U2OS cell migration rates of Ad5-Herg1-shRNA1 and Ad5-Herg1-shRNA2 group were 21.83±7.99 and 22.85±7.08, significantly lower than 83.33±12.36 of Ad5-control-shRNA group (all P<0.001). The results of xenograft model of OS showed that the tumor volume and weight of Ad5-Herg1-shRNA group were significantly smaller than of Ad5-control-shRNA group after 14 days and 5 weeks of inoculation, respectively (P<0.001). Moreover, knockdown of Herg1 inhibited the metastasis of OS cells. In mechanism, Herg1 protein interacted with NF2 protein. Knockdown of Herg1 significantly suppressed the expression levels of LATS1 and YAP protein, and promoted the phosphorylation of LATS1 and YAP in OS cells (all P<0.001). Conclusion: Our findings suggest that Herg1 participates in the proliferation and motility of OS cells and may serve as a potential therapeutic target for osteosarcoma patients.


Assuntos
Neoplasias Ósseas/genética , Canal de Potássio ERG1/genética , Osteossarcoma/genética , Proteínas Serina-Treonina Quinases/metabolismo , Adenoviridae , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação para Baixo , Vetores Genéticos , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Transdução de Sinais , Transplante Heterólogo
15.
Mol Med Rep ; 20(1): 292-302, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115575

RESUMO

Increasing amounts of long noncoding RNAs (lncRNAs) have been shown to be involved in the development of cancer. Recently, aberrant expression of the lncRNA forkhead box D2 adjacent opposite strand RNA1 (FOXD2­AS1) has been reported to be involved in the progression of several types of human cancer. However, the function and mechanism of FOXD2­AS1 in osteosarcoma (OS) are currently unclear. The present study aimed to investigate the function and mechanism of FOXD2­AS1 in OS. Firstly, it was revealed that the expression levels of FOXD2­AS1 were significantly upregulated in OS tissues and cells, compared with in adjacent tissues and normal cells, as determined using reverse transcription­quantitative polymerase chain reaction. Notably, the overall survival of patients with relatively high FOXD2­AS1 expression in OS tissues was significantly lower than that of patients with relatively low expression, as determined using Kaplan­Meier analysis. In addition, loss­of­function experiments were performed in vivo and in vitro to study the biological effects of FOXD2­AS1. The SOSP­9607 and U2OS OS cell lines were infected with lentivirus­mediated FOXD2­AS1 short hairpin RNA; subsequently, the alterations in cell phenotype and downstream molecules were evaluated. Knockdown of FOXD2­AS1 inhibited the proliferation, migration and invasion of OS cells. Furthermore, the number of cells in the S phase was significantly decreased, which was consistent with the results of the Cell Counting kit 8 proliferation assay. The expression levels of ribonucleotide reductase regulatory subunit M2 and phosphoglycerate dehydrogenase were decreased, as determined by western blotting, following FOXD2­AS1 knockdown. Finally, in a nude mouse model of tumorigenesis, it was revealed that, when FOXD2­AS1 expression was downregulated, tumor growth was significantly reduced and pulmonary metastatic nodules were markedly reduced. The results of the present study suggested that decreased FOXD2­AS1 expression may inhibit the growth, migration and invasion of tumor cells, and it may regulate downstream gene expression. In conclusion, these findings indicated that FOXD2­AS1 may be used as a potential therapeutic target and early tumor marker for the diagnosis and prognosis of OS.


Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Osteossarcoma/genética , RNA Longo não Codificante/genética , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Criança , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Osteossarcoma/patologia , Prognóstico , Adulto Jovem
16.
Int J Clin Oncol ; 24(8): 976-982, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111286

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor in young adults and adolescents with approximately 3 million new cases annually. Due to the lack of sensitive and specific diagnostic biomarkers, although OS patients are curable after surgical resection, many patients suffer from metastasis or recurrence. This study aimed to investigate whether circulating microRNAs (miRNAs) could serve as biomarkers for the diagnosis of OS. MATERIALS AND METHODS: Healthy individuals and OS patients enrolled in this study came from Nanjing First Hospital. First, candidate miRNAs were selected by integrated analysis of two GEO datasets and a publicly available miRNA dataset. The expression of these miRNAs in tissues and serum samples were subsequently examined through qRT-PCR. The diagnostic utility of these differential miRNAs was examined by using receiver operating characteristic (ROC) curve analysis. Finally, the potential signaling pathways associated with candidate miRNAs were searched through online tools. RESULTS: Four miRNAs (miR-487a, miR-493-5p, miR-501-3p and miR-502-5p) were selected to further investigate their diagnostic potential for OS. We discovered miR-487a, miR-493-5p, miR-501-3p and miR-502-5p were upregulated in OS tissues and serums. Besides, miR-487a, miR-493-5p, miR-501-3p and miR-502-5p in peripheral blood of OS patients were tumor-derived. The area under the ROC curve (AUC) was 0.83 (95% CI 0.71-0.97) for miR-487a, 0.79 (95% CI 0.66-0.93) for miR-493-5p, 0.82 (95% CI 0.68-0.95) for miR-501-3p, 0.83 (95% CI 0.72-0.95) for miR-502-5p, and 0.89 (95% CI 0.78-1.0) for miRNAs combination. CONCLUSION: Circulating miR-487a, miR-493-5p, miR-501-3p and miR-502-5p were novel potential diagnostic biomarkers of OS.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/diagnóstico , MicroRNAs/genética , Osteossarcoma/diagnóstico , Adolescente , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/sangue , Osteossarcoma/sangue , Osteossarcoma/genética , Prognóstico , Curva ROC
17.
J Exp Clin Cancer Res ; 38(1): 226, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138318

RESUMO

BACKGROUND/AIMS: A novel paradigm in tumor biology suggests that osteosarcoma (OS) chemo-resistance is driven by osteosarcoma stem cell-like cells (OSCs). As the sensitivity of only a few tumors to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can be explained by the presence of EGFR tyrosine kinase (TK) domain mutations, there is a need to elucidate mechanisms of resistance to EGFR-targeted therapies in OS that do not harbor TK sensitizing mutations to develop new strategies to circumvent resistance to EGFR inhibitors. METHODS: As a measure of the characters of OSCs, serum-free cultivation, cell viability test with erlotinib, and serial transplantation in vivo was used. Western blot assays were used to detect the association between erlotinib resistance and transforming growth factor beta (TGFß)-induced epithelial-to-mesenchymal transition (EMT) progression. By using TaqMan qPCR miRNA array, online prediction software, luciferase reporter assays and western blot analysis, we further elucidated the mechanisms. RESULTS: Here, CD166+ cells are found in 10 out of 10 tumor samples. We characterize that CD166+ cells from primary OS tissues bear hallmarks of OSCs and erlotinib-resistance. TGFß-induced EMT-associated kinase switch is demonstrated to promote erlotinib-resistance of CD166+ OSCs. Further mechanisms study show that TGFß-induced EMT decreases miR-499a expression through the direct binding of Snail1/Zeb1 to miR-499a promoter. Overexpression of miR-499a in CD166+ OSCs inhibits TGFß-induced erlotinib-resistance in vitro and in vivo. SHKBP1, the direct target of miR-499a, regulates EGFR activity reduction occurring concomitantly with a TGFß-induced EMT-associated kinase switch to an AKT-activated EGFR-independent state. TGFß-induced activation of AKT co-opts an increased SHKBP1 expression, which further regulates EGFR activity. In clinic, the ratio of the expression levels of SHKBP1 and miR-499a is highly correlated with EMT and resistance to erlotinib. CONCLUSION: TGFß-miR-499a-SHKBP1 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors in CD166+ OSCs, implies that inhibition of TGFß induced EMT-associated kinase switch may reverse the chemo-resistance of OSCs to EGFR inhibitors. We also suggest that an elevated SHKBP1/miR-499a ratio is a molecular signature that characterizes the erlotinib-resistant OS, which may have clinical value as a predictive biomarker.


Assuntos
Neoplasias Ósseas/patologia , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/citologia , Osteossarcoma/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro/química , Transição Epitelial-Mesenquimal , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Osteossarcoma/genética , Osteossarcoma/metabolismo , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Regulação para Cima
18.
Nat Commun ; 10(1): 2226, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110221

RESUMO

Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.


Assuntos
Carcinogênese/genética , Polpa Dentária/citologia , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , PTEN Fosfo-Hidrolase/metabolismo , Adipócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Carcinogênese/patologia , Diferenciação Celular/genética , Células Cultivadas , Criança , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Polpa Dentária/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/metabolismo , Código das Histonas/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética , Análise de Sequência de RNA
19.
Medicine (Baltimore) ; 98(21): e15793, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124974

RESUMO

BACKGROUND: Since long non-coding RNA breast cancer anti-estrogen resistance 4 (lncRNA BCAR4) is dysregulated in various types of cancers, we conducted a meta-analysis to determine its prognostic value in cancer. METHODS: PubMed, EMBASE database, and CENTRAL were systematically searched.Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were collected to estimate the prognostic value. Odds ratios (ORs) and their 95% CIs were used to assess the association between lncRNA BCAR4 expression and clinicopathological features, including tumor size, differentiation, lymph node metastasis, distant metastasis, and tumor stage. RESULTS: Ten studies with 890 patients were included in this meta-analysis. The pooled results indicated that high lncRNA BCAR4 expression was associated with poor overall survival (OS) (HR 2.80, 95% CI: 2.08-3.78; P < .001). Overexpression of lncRNA BCAR4 was related to lymph node metastasis (OR 3.68, 95% CI: 2.25-6.00; P < .001), high tumor stage (OR 3.19, 95% CI: 1.98-5.13; P < .001), and distant metastasis (OR 3.83, 95% CI: 2.15-6.82; P < .001), but not to tumor size. CONCLUSIONS: Therefore, lncRNA BCAR4 overexpression is associated with poor OS and advanced clinicopathological features, and lncRNA BCAR4 may be a novel prognostic biomarker in cancer patients. However, further high-quality studies are needed to confirm these findings.


Assuntos
Neoplasias/genética , Neoplasias/mortalidade , RNA Longo não Codificante/análise , Adulto , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Metástase Linfática/genética , Pessoa de Meia-Idade , Osteossarcoma/genética , Osteossarcoma/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade
20.
Life Sci ; 229: 225-232, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085244

RESUMO

AIMS: Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells. MATERIALS AND METHODS: Knockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-ß-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS). SIGNIFICANCE: Our results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.


Assuntos
Neoplasias Ósseas/patologia , Senescência Celular , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Osteossarcoma/patologia , Fatores de Transcrição/metabolismo , Células A549 , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Células NIH 3T3 , Osteossarcoma/genética , Osteossarcoma/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética
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