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1.
Medicine (Baltimore) ; 100(14): e24118, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832059

RESUMEN

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.


Asunto(s)
Neoplasias Óseas/genética , Osteosarcoma/genética , ARN Mensajero/metabolismo , Adolescente , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/mortalidad , Niño , Bases de Datos Factuales , Femenino , Humanos , Masculino , Osteosarcoma/mortalidad , Curva ROC , Análisis de Secuencia de ARN , Transcriptoma
2.
Braz J Med Biol Res ; 54(6): e10474, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33886809

RESUMEN

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.


Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Neoplasias Óseas/genética , Caveolina 1/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Osteosarcoma/genética
3.
Zhonghua Zhong Liu Za Zhi ; 43(4): 457-465, 2021 Apr 23.
Artículo en Chino | MEDLINE | ID: mdl-33902208

RESUMEN

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.


Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Proteína 7 Relacionada con la Autofagia , Neoplasias Óseas/genética , Línea Celular Tumoral , Proliferación Celular , Humanos , MicroARNs/genética , Osteosarcoma/genética
4.
Medicine (Baltimore) ; 100(12): e24765, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761638

RESUMEN

ABSTRACT: MicroRNA (miR)-26a-5p is an oncogene significantly associated with osteosarcoma. We try to evaluate expression of circulating miR-26a-5p in osteosarcoma patients and evaluate its significance.A total of 243 consecutive osteosarcoma patients and 96 healthy participates were enrolled. Circulating miR-26a-5p levels were evaluated by using real-time quantitative reverse transcription polymerase chain reactions (RT-PCR). The association between circulating miR-26a-5p level and survival outcomes was evaluated by univariate and multivariate analysis.Circulating miR-26a-5p levels in osteosarcoma patients was significantly higher than that of healthy volunteers (P < .05). Upregulated miR-26a-5p was significantly related to advanced cancer and metastasis (both P < .05). Moreover, patients with a high serum miR-26a-5p had a poorer overall survival than those with a low serum miR-26a-5p levels (P < .05). Circulating miR-26a-5p level also been showed as independent risk factor for osteosarcoma in multivariate analysis (hazard ratio [HR], 0.38; 95% confidence interval [CI]: 0.11-0.98; P < .01).Circulating miR-26a-5p was significantly upregulated in osteosarcoma patients and remarkably associated with poor prognosis, indicating that circulating miR-26a-5p might serve as a useful diagnostic and prognostic biomarker for osteosarcoma.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/mortalidad , MicroARN Circulante/metabolismo , MicroARNs/metabolismo , Recurrencia Local de Neoplasia/epidemiología , Osteosarcoma/mortalidad , Adulto , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/genética , Neoplasias Óseas/cirugía , MicroARN Circulante/sangre , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Biopsia Líquida , Masculino , MicroARNs/sangre , Recurrencia Local de Neoplasia/genética , Osteosarcoma/sangre , Osteosarcoma/genética , Osteosarcoma/cirugía , Estudios Retrospectivos , Medición de Riesgo/métodos , Regulación hacia Arriba , Adulto Joven
5.
Medicine (Baltimore) ; 100(11): e24818, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725949

RESUMEN

ABSTRACT: Osteosarcoma is a malignant tumor that develops from a mesenchymal cell line and is caused by gene-environment interactions. This study aimed to explore whether TIMP2/TIMP3 polymorphisms influenced the osteosarcoma risk.The expression of the TIMP2 and TIMP3 genes in osteosarcoma histiocytes was analyzed by immunohistochemistry. In this case-control study, which includes samples from 499 patients and 500 healthy controls, 10 single-nucleotide polymorphisms (SNPs) in TIMP2 and TIMP3 were selected. Furthermore, we used the Agena MassARRAY platform for genotyping. The statistical analysis was performed using χ2 test/Fisher exact test, and logistic regression analysis.The immunohistochemistry results showed that the expression of TIMP2 is obvious higher in osteosarcoma histiocytes than in the normal histiocytes. The association study indicated that the allele of rs2277698 and rs4789936 were protective SNPs reducing the risk of osteosarcoma (odds ratios  > 1, P < .05) by the χ2 test. In the genetic model, logistic regression analyses revealed that the rs2277698 and rs4789936 were associated with decreasing the risk of osteosarcoma under the codominant model, dominant model, and log-additive model. Stratification analysis revealed that 2 SNPs (rs2277698 and rs4789936) were significantly associated with a reduced risk of osteosarcoma in allele and genetic model after stratification by gender or age (P < .05). In addition, the haplotype "Trs2277698Crs2009169Crs7342880" of TIMP2 was associated with decreasing the osteosarcoma risk. The "Ars9609634Trs11547635" of TIMP3 was associated with reducing the osteosarcoma risk.This finding shed new light on the high expression of TIMP2 polymorphisms may contribute to decreasing the osteosarcoma risk in Zhejiang populations.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Neoplasias Óseas/genética , Osteosarcoma/genética , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-3/genética , Adolescente , Anciano , Alelos , Neoplasias Óseas/etnología , Estudios de Casos y Controles , China/etnología , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos , Humanos , Inmunohistoquímica , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Osteosarcoma/etnología , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Adulto Joven
6.
BMC Cancer ; 21(1): 210, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648449

RESUMEN

BACKGROUND: A number of studies have linked positive Ki-67 expression with the prognosis of osteosarcoma (OS) patients. However, the results have been conflicting. To address this controversy, we conducted an analysis using a meta-analysis and a TCGA dataset to estimate the value of Ki-67 expression in the prognosis of OS. METHODS: A comprehensive search for relevant papers was conducted using NCBI PubMed, Embase, Springer, ISI Web of Knowledge, the Cochrane Library, and CNKI regardless of the publication year. The associations between Ki-67 expression and the clinical features and main prognostic outcomes of OS were measured. The TCGA dataset was also analyzed. The pooled odds ratio (OR) and its 95% confidential intervals (CIs) were utilized for statistical analysis. RESULTS: Overall, a total of 12 studies with 500 cases were included, and the results indicated that the expression of Ki-67 was significantly associated with Enneking stage (OR = 6.88, 95% CI: 2.92-16.22, p < 0.05), distant metastasis (OR = 3.04, 95% CI: 1.51-6.12, p < 0.05) and overall survival (OR = 8.82, 95% CI: 4.68-16.65, p < 0.05) in OS patients. Additionally, we observed no significant heterogeneity among all retrieved studies. Associations between Ki-67 expression and overall survival and disease-free survival of sarcoma were confirmed using the TCGA and Kaplan-Meier plotter datasets. CONCLUSION: The present study strongly suggests that positive Ki-67 expression was associated with Enneking stage, distant metastasis, and overall survival of OS, and it may be used as a potential biomarker to predict prognosis and guide clinical therapy for OS.


Asunto(s)
Antígenos de Neoplasias/análisis , Neoplasias Óseas/metabolismo , Antígeno Ki-67/análisis , Osteosarcoma/metabolismo , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/genética , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/biosíntesis , Antígeno Ki-67/genética , Metástasis de la Neoplasia , Estadificación de Neoplasias , Osteosarcoma/genética , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Sesgo de Publicación , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/mortalidad , Sarcoma/patología , Regulación hacia Arriba
7.
Medicine (Baltimore) ; 100(6): e24471, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578541

RESUMEN

BACKGROUND: In osteosarcoma, the lung is the most common metastatic organ. Intensive work has been made to illuminate the pathogeny, but the specific metastatic mechanism remains unclear. Thus, we conducted the study to seek to find the key genes and critical functional pathways associated with progression and treatment in lung metastasis originating from osteosarcoma. METHODS: Two independent datasets (GSE14359 and GSE85537) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform. Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were conducted using DAVID. Meanwhile, the protein-protein interaction (PPI) network constructed by STRING was visualized using Cytoscape. Afterwards, the key module and hub genes were extracted from the PPI network using the MCODE and cytoHubba plugin. Moreover, the raw data obtained from GSE73166 and GSE21257 were applied to verify the expression differences and conduct the survival analyses of hub genes, respectively. Finally, the interaction network of miRNAs and hub genes constructed by ENCORI was visualized using Cytoscape. RESULTS: A total of 364 DEGs were identified, comprising 96 downregulated genes and 268 upregulated genes, which were mainly involved in cancer-associated pathways, adherens junction, ECM-receptor interaction, focal adhesion, MAPK signaling pathway. Subsequently, 10 hub genes were obtained and survival analysis demonstrated SKP2 and ASPM were closely related to poor prognosis of patients with osteosarcoma. Finally, hsa-miR-340-5p, has-miR-495-3p, and hsa-miR-96-5p were found to be most closely associated with these hub genes according to the interaction network of miRNAs and hub genes. CONCLUSION: The key genes and functional pathways identified in the study may contribute to understanding the molecular mechanisms involved in the carcinogenesis and progression of lung metastasis originating from osteosarcoma, and provide potential diagnostic and therapeutic targets.


Asunto(s)
Neoplasias Óseas/patología , Neoplasias Pulmonares/secundario , Osteosarcoma/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Genes Relacionados con las Neoplasias/genética , Marcadores Genéticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosarcoma/diagnóstico , Osteosarcoma/genética , Transducción de Señal/genética
8.
J Biol Regul Homeost Agents ; 35(1): 151-160, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543608

RESUMEN

Osteosarcoma (OS) is the most frequent primary malignancy in bone, and commonly occurs in children and adolescents. The aim of this study was to assess the aberrant expression of miR-1274a in OS patients, and to evaluate the role of miR-1274a as a prognostic biomarker and tumor suppressor in OS progression. miR-1274a expression was estimated using quantitative real-time polymerase chain reaction. The Kaplan-Meier method and Cox regression analysis were used to evaluate the prognostic value of miR-1274a in OS. Gain- and loss-of-function in vitro experiments were used to explore the functional role of miR-1274a in OS progression. A target gene of miR-1274a was analyzed using a dual-luciferase reporter assay. miR-1274a expression was decreased in OS tissues and associated with distant metastasis and clinical stages in OS patients. Low miR-1274a could predict poor overall survival and disease-free survival in OS. The overexpression of miR-1274a could inhibit OS cell proliferation, migration and invasion. Additionally, ADAM9 was demonstrated to serve as a direct target of miR-1274a in OS cells. In conclusion, reduced miR-1274a predicts poor prognosis and serves as a potential tumor suppressor in OS. ADAM9 is a target of miR-1274a, which may mediate the functional role of miR-1274a in OS progression.


Asunto(s)
Neoplasias Óseas , MicroARNs/genética , Osteosarcoma , Proteínas ADAM , Biomarcadores , Neoplasias Óseas/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana , Invasividad Neoplásica/genética , Osteosarcoma/genética , Pronóstico
9.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540580

RESUMEN

Cancer cell metabolism is dependent on cell-intrinsic factors, such as genetics, and cell-extrinsic factors, such nutrient availability. In this context, understanding how these two aspects interact and how diet influences cellular metabolism is important for developing personalized treatment. In order to achieve this goal, genome-scale metabolic models (GEMs) are used; however, genetics and nutrient availability are rarely considered together. Here, we propose integrated metabolic profiling, a framework that allows enriching GEMs with metabolic gene expression data and information about nutrients. First, the RNA-seq is converted into Reaction Activity Score (RAS) to further scale reaction bounds. Second, nutrient availability is converted to Maximal Uptake Rate (MUR) to modify exchange reactions in a GEM. We applied our framework to the human osteosarcoma cell line (U2OS). Osteosarcoma is a common and primary malignant form of bone cancer with poor prognosis, and, as indicated in our study, a glutamine-dependent type of cancer.


Asunto(s)
Neoplasias Óseas/metabolismo , Glutamina/metabolismo , Metabolómica , Osteosarcoma/metabolismo , RNA-Seq , Neoplasias Óseas/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Osteosarcoma/genética
10.
Gene ; 782: 145537, 2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-33636294

RESUMEN

Detection of TCGA data revealed that WIPI1 is highly expressed in osteosarcoma cells. So we explore the mechanisms of WIPI1 affecting the proliferation of osteosarcoma cells through Affymetrix microarray analysis. Functional analysis of differentially expressed genes shows that the classical signaling pathways affecting tumor formation and development have changed significantly. By fitting analysis, it is speculated that the WIPI1 may function in the direction of osteosarcoma by regulating the expression of multiple cell cycle-related genes such as CDKN1A, CDK4 and CCND1. Therefore, the key genes are selected for RT-PCR and Western-blot verification. Combined with flow and other means, WIPI1 may affect the cell cycle and the osteosarcoma by regulating the expression of CDKN1A, CDK4 and CCND1. To verify the results, the effect of WIPI1 on cell proliferation was quantified by MTT, cell counts and nude mouse tumorigenicity assay. The results showed that WIPI1 promotes osteosarcoma cell proliferation.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Neoplasias Óseas/genética , Proliferación Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Proteínas de la Membrana/genética , Osteosarcoma/genética , Animales , Proteínas Relacionadas con la Autofagia/fisiología , Neoplasias Óseas/patología , Ciclo Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Vectores Genéticos , Células HEK293 , Humanos , Lentivirus/genética , Proteínas de la Membrana/fisiología , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteosarcoma/patología , Programas Informáticos , Transcriptoma
12.
Environ Toxicol ; 36(6): 1090-1098, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33543840

RESUMEN

The promoting roles of the transcriptional regulator SMAR1 have been revealed in several tumors, such as colorectal and breast cancer, however, its roles in osteosarcoma (OS) progression are still confusing. Here, we find that SMAR1 expression is positively correlated with the overall survival of OS patients and negatively correlated with the expression of stemness markers by analyzing the online datasets. Through analyzing different Gene Expression Omnibus (GEO) datasets, SMAR1 is found to be lowly expressed in OS tissues relative to that in adjacent tissues. Functional experiments indicate that SMAR1 overexpression attenuates the stemness of OS cells, characterized as the decrease of stemness marker expression, sphere-formation ability and ALDH activity. Mechanistically, it is shown that SMAR1 increases the deacetylation level of the drug efflux pump ABCG2 via recruiting HDAC2 to the promoter of the gene coding ABCG2, and thus decreases ABCG2 transcriptional activity. Additionally, overexpression of ABCG2 rescues the inhibition of SMAR1 overexpression on the stemness of OS cells. Moreover, this SMAR1/ABCG2 axis positively regulates the chemotherapeutic sensitivity of OS cells. This work indicates that SMAR1 is a critical suppressor for OS progression through transcriptionally regulating ABCG2 expression.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/genética , Osteosarcoma/genética
13.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(2): 285-291, 2021 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-33624604

RESUMEN

OBJECTIVE: To investigate the effects of miR-300 and PTTG1 on osteosarcoma invasion and metastasis and explore the molecular mechanism of osteosarcoma invasion and metastasis. OBJECTIVE: Western blot was used to detect the expression of PTTG1 in human osteoblasts hFOB1.19 and osteosarcoma cell MG63 and to detect the transfection efficiency of cells transfected with PTTG1-knockdown plasmid; Transwell invasion assay and CCK8 assay detected the effects of knockdown of PTTG1 and overexpression of miR-300 on the invasion and proliferation of osteosarcoma cell MG63. On-line prediction and screening of microRNAs (miRNAs) with complementary PTTG1 binding was conducted. qRT-PCR was performed to examine the expression of miR-300 in hFOB1.19 and MG63 cells, and Western blotting was used to detect the expression of PTTG1 in MG63 cells after transfection with a miR- 300 plasmid. Double luciferase assay was used to detect the targeted binding of miR-300 and PTTG, Transwell invasion assay and CCK8 assay were used to detect the effects of overexpression of miR-300 and overexpression of PTTG1 plasmid on invasion and proliferation of osteosarcoma cell line MG63. OBJECTIVE: PTTG1 was highly expressed in MG63 cells (P=0.0002). PTTG1 knockdown significantly inhibited the invasion (P=0.0002) and proliferation (P=0.0039) of MG63 cells. Based on the results of online prediction of complementary miRNAs to PTTG1 and analysis of the data from NCBI database, miR-300 was determined as the target miRNA in this study. qRT-PCR results showed a significantly decreased expression of miR-300 in MG63 cells (P=0.0004). Overexpression of MiR-300 in MG63 cells significantly decreased the expression of PTTG1 (P=0.0007), and the expressions of miR-300 and PTTG1 were negatively correlated. Dual luciferase assay showed that miR-300 could specifically bind to PTTG1 (P=0.001). Overexpression of PTTG1 could significantly reverse the effect of miR-300 overexpression on invasion (P=0.0003) and proliferation (P=0.0077) of MG63 cells. OBJECTIVE: Overexpression of miR-300 can inhibit the invasion and metastasis of osteosarcoma cell MG63 by targeting PTTG1.


Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Neoplasias Óseas/genética , Línea Celular Tumoral , Proliferación Celular , Humanos , MicroARNs/genética , Osteosarcoma/genética , Securina
14.
BMC Cancer ; 21(1): 202, 2021 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-33639865

RESUMEN

BACKGROUND: In recent years, emerging studies have demonstrated critical functions and potential clinical applications of long non-coding RNA (lncRNA) in osteosarcoma. To further validate the prognostic value of multiple lncRNAs, we have conducted this updated meta-analysis. METHODS: Literature retrieval was conducted by searching PubMed, Web of Science and the Cochrane Library (last update by October 2, 2019). A meta-analysis was performed to explore association between lncRNAs expression and overall survival (OS) of osteosarcoma patients. Relationships between lncRNAs expression and other clinicopathological features were also analyzed respectively. RESULTS: Overall, 4351 patients from 62 studies were included in this meta-analysis and 25 lncRNAs were identified. Pooled analyses showed that high expression of 14 lncRNAs connoted worse OS, while two lncRNAs were associated with positive outcome. Further, analysis toward osteosarcoma clinicopathologic features demonstrated that overexpression of TUG1 and XIST indicated poor clinical parameters of patients. CONCLUSIONS: This meta-analysis has elucidated the prognostic potential of 16 lncRNAs in human osteosarcoma. Evidently, desperate expression and functional targets of these lncRNAs offer new approaches for prognosis and therapy of osteosarcoma.


Asunto(s)
Neoplasias Óseas/sangre , Osteosarcoma/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Biomarcadores de Tumor , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Osteosarcoma/genética , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Sesgo de Publicación
15.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503899

RESUMEN

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.


Asunto(s)
Neoplasias Óseas/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Osteosarcoma/genética , Transcriptoma , Biomarcadores , Biopsia , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Osteosarcoma/metabolismo , Osteosarcoma/patología
16.
Braz J Med Biol Res ; 54(2): e9161, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33439936

RESUMEN

Patients with osteosarcoma (OS) usually have poor overall survival because of frequent metastasis. Long non-coding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and metastasis. In this study, we investigated the expression and roles of lncRNA human histocompatibility leukocyte antigen (HLA) complex P5 (HCP5) in OS, aiming to provide a novel molecular mechanism for OS. HCP5 was up-regulated both in OS tissues and cell lines and high expression of HCP5 was associated to low survival in OS patients. Down-regulation of HCP5 inhibited cell proliferation, migration, and invasion, suggesting its carcinogenic role in OS. miR-101 was targeted by HCP5 and its expression was decreased in OS. The inhibitor of miR-101 reversed the impact of HCP5 down-regulation on cell proliferation, apoptosis, and metastasis in OS. Ephrin receptor 7 (EPHA7) was proved to be a target of miR-101 and had ability to recover the effects of miR-101 inhibitor in OS. In conclusion, lncRNA HCP5 knockdown suppressed cell proliferation, migration, and invasion, and induced apoptosis through depleting the expression of EPHA7 by binding to miR-101, providing a potential therapeutic strategy of HCP5 in OS.


Asunto(s)
Neoplasias Óseas , MicroARNs/metabolismo , Osteosarcoma , ARN Largo no Codificante/genética , Receptor EphA7/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Osteosarcoma/genética , Osteosarcoma/patología
17.
Anticancer Res ; 41(2): 635-640, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517267

RESUMEN

BACKGROUND: A mouse model of metastatic osteosarcoma is imperative to identify effective agents for metastatic osteosarcoma, which is a recalcitrant disease. In the present study, we established osteosarcoma patient-derived cells (OS-PDCs) and transfected them with green fluorescent protein (GFP). MATERIALS AND METHODS: The OS-PDCs were transfected with GFP-lentivirus. GFP-expressing OS-PDCs (2.0×105) were then injected into the tibia of nude mice to establish the patient-derived orthotopic cell (PDOC) model (n=3). Six weeks after injection, the primary tumor and each organ were resected and imaged. RESULTS: Primary orthotopic tumors were established in two out of three mice. The GFP-expressing OS-PDCs in the PDOC model were visualized. Multiple GFP-expressing lung metastases were detected in one of the two mice with primary tumor. CONCLUSION: The present study proves the concept that a GFP-expressing PDOC model can mimic clinical lung-metastatic osteosarcoma. This model can serve as a paradigm to screen for effective drugs for osteosarcoma lung metastasis.


Asunto(s)
Neoplasias Óseas/patología , Proteínas Fluorescentes Verdes/metabolismo , Neoplasias Pulmonares/secundario , Osteosarcoma/secundario , Tibia/patología , Adolescente , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Rastreo Celular , Femenino , Proteínas Fluorescentes Verdes/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones Desnudos , Trasplante de Neoplasias , Osteosarcoma/genética , Osteosarcoma/metabolismo , Tibia/metabolismo , Transfección , Células Tumorales Cultivadas
18.
Life Sci ; 268: 118925, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33358903

RESUMEN

AIMS: Osteosarcoma (OS) is an extremely malignant bone cancer with high incidence and rapid progression. This study aims to investigate the role and underlying mechanisms of MALAT1 and miR-485-3p in OS. MATERIALS AND METHODS: qRT-PCR and Western blotting were utilized to measure the levels of miR-485-3p, MALAT1, c-MET, AKT3, p-mTOR, mTOR, glycolysis-related proteins or migration-related proteins. Colony formation and transwell assay were used to test the roles of miR-485-3p, MALAT1, c-MET and AKT3 in cancer cell proliferation, migration and invasion. Dual luciferase assay was used to validate the interactions of miR-485-3p/c-MET, miR-485-3p/AKT3, and MALAT1/miR-485-3p. Glucose uptake assay and measurement of lactate production were employed to determine the glycolysis process. Mouse tumour xenograft model was used to determine the effect of shMALAT1 and miR-485-3p mimics on tumour growth and metastasis in vivo. KEY FINDINGS: miR-485-3p was decreased while c-MET, AKT3, and MALAT1 were increased in human OS tissues and cells. miR-485-3p bound directly to c-MET and AKT3 mRNAs and repressed OS cell glycolysis, proliferation, migration, and invasion through decreasing glycolysis-related proteins and migration-related proteins via inhibiting c-MET and AKT3/mTOR pathway. In addition, MALAT1 interacted with miR-485-3p and disinhibited c-MET and AKT3/mTOR signalling. Knockdown MALAT1 or overexpression of miR-485-3p restrained OS tumour growth and lung metastasis in vivo. SIGNIFICANCE: miR-485-3p suppresses OS glycolysis, proliferation, and metastasis via inhibiting c-MET and AKT3/mTOR signalling and MALAT1 acts as a sponge of miR-485-3p. MALAT1 and miR-485-3p may be the key regulators in OS progression, and potential molecular targets for future OS therapy.


Asunto(s)
Neoplasias Óseas/patología , MicroARNs/genética , Osteosarcoma/patología , Proteínas Proto-Oncogénicas c-met/genética , ARN Largo no Codificante/genética , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glucólisis/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Osteosarcoma/genética , Osteosarcoma/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Environ Toxicol ; 36(5): 773-781, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33325610

RESUMEN

Butein is a flavonoid isolated from various medicinal plants. It is known to have different biological activities including anti-inflammation, anti-adipogenesis, and anti-angiogenesis. In the study, we demonstrated the anti-proliferative effect of butein in human osteosarcoma U-2 OS cells. Our data showed that butein significantly suppressed the viability and colony formation ability of U-2 OS cells. Further experiments revealed butein exposure resulted in a cell cycle arrest at S and G2/M phase in U-2 OS cells. Importantly, we found that butein activated the tumor suppressor p53, and trigged a p53-dependent senescence in U-2 OS cells. Knockdown of p53 suppressed the senescence and rescued the viability in butein-treated U-2 OS cells. Furthermore, we observed that butein exposure significantly enhanced reactive oxygen species (ROS) levels in U-2 OS cells. Co-administration of the ROS inhibitor NAC largely abolished the up-regulated p53 protein level, and rescued the suppressed viability and colony formation ability in butein-exposed U-2 OS cells. Taken together, our data proposed the increased ROS by butein exposure activated p53, and the activated p53 was involved in the anti-proliferative effect of butein via inducing senescence in U-2 OS cells. This report suggests that butein is a promising candidate for cancer therapy against osteosarcoma.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Apoptosis , Línea Celular Tumoral , Senescencia Celular , Chalconas , Humanos , Osteosarcoma/genética , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/genética
20.
Exp Mol Pathol ; 118: 104596, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33347862

RESUMEN

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) exhibits a variety of biological responses. In tumor microenvironment, endothelial cells promote cancer cell functions. In this study, we investigated the roles of endothelial cells in the regulation of cell motile activity via LPA2 and LPA3 in human osteosarcoma MG-63 cells. In cell motility assay, the cell motile activity of MG-63 cells was markedly increased by the supernatants of endothelial F2 cells. MG-63 cell motility elevated by the supernatants was enhanced by GRI-977143 (LPA2 agonist) and reduced by (2S)-OMPT (LPA3 agonist). LPAR2 and LPAR3 expressions were increased in highly migratory MG63-CR7(F2) cells, which were generated from MG-63 cells by co-culture with F2 cell supernatants. MG63-CR7(F2) cell motility was stimulated by LPA treatment. In the presence of F2 cell supernatants, MG63-CR7(F2) cell motility was markedly enhanced by GRI-977143 and suppressed by (2S)-OMPT. Autotaxin (ATX) enzymatically converts lysophosphatidylcholine (LPC) to LPA. ATX expression was higher in MG63-CR(F2) cells than in MG-63 cells. MG63-CR7(F2) cell motility was markedly increased by LPC in comparison with MG-63 cells. In addition, MG63-CR(F2) cell motility was significantly stimulated by the supernatants of LPC treated F2 cells. The present results suggest that the activation of LPA signaling via LPA2 and LPA3 by endothelial cells is involved in the modulation of cell motile activity of MG-63 cells.


Asunto(s)
Neoplasias Óseas/patología , Movimiento Celular , Células Endoteliales/patología , Regulación Neoplásica de la Expresión Génica , Osteosarcoma/patología , Receptores del Ácido Lisofosfatídico/metabolismo , Apoptosis , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Proliferación Celular , Células Endoteliales/metabolismo , Humanos , Lisofosfolípidos/metabolismo , Osteosarcoma/genética , Osteosarcoma/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Transducción de Señal , Células Tumorales Cultivadas
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