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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.
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
3.
Nat Commun ; 12(1): 1714, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731701

RESUMEN

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-ß induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.


Asunto(s)
Neoplasias Óseas/secundario , Carcinogénesis , Transición Epitelial-Mesenquimal , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Acetilación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencilaminas/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Ciclamas/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Mutación , Osteogénesis , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo
4.
Medicine (Baltimore) ; 100(8): e24917, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33663128

RESUMEN

RATIONALE: Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance. PATIENT CONCERNS: A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again. DIAGNOSIS: The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma. INTERVENTIONS: Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again. OUTCOMES: Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient's resistance to lorlatinib. LESSONS: We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Neoplasias Óseas/secundario , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Proteínas de Ciclo Celular , Crizotinib/farmacología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resultado Fatal , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina Endopeptidasas
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.
Zhonghua Bing Li Xue Za Zhi ; 50(3): 190-193, 2021 Mar 08.
Artículo en Chino | MEDLINE | ID: mdl-33677880

RESUMEN

Objective: To investigate the subtypes of H3F3A DNA mutation in H3.3 immunohistochemistry (IHC) negative giant cell tumors of bone (GCTB). Methods: IHC expression of G34W mutated protein was evaluated in 181 cases GCTB. In H3.3 IHC negative cases, Sanger DNA sequencing analysis was used to detect the subtypes H3F3A mutations. Results: Overall, 164 (90.61%) cases of GCTB showed nuclear expression of H3.3, and 17 cases were negative. These 17 H3.3 negative cases were subjected to Sanger DNA sequencing analysis; results showed that eight presented rare mutation subtypes occurring at glycine 34 to leucine (G34L, 3/181, 1.66%), glycine 34 to valine (G34V, 3/181, 1.66%) and glycine 34 to arginine (G34R, 2/181, 1.10%), and the other nine cases were wild type (glycine 34, 9/181, 4.97%). Sanger DNA sequencing analysis confirmed the absence of G34W mutation in the H3.3 negative cases. Combining IHC and DNA sequencing analysis increased the detection rate of H3F3A mutation in the GCTB to 95.03%. Conclusions: H3.3 IHC could detect H3F3A G34W mutation in GCTB, but not for other rare mutation and wild types loci.


Asunto(s)
Neoplasias Óseas , Tumor Óseo de Células Gigantes , Neoplasias Óseas/genética , Tumor Óseo de Células Gigantes/diagnóstico , Tumor Óseo de Células Gigantes/genética , Histonas/genética , Humanos , Inmunohistoquímica , Mutación , Análisis de Secuencia de ADN
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.
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
9.
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
10.
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
11.
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
12.
Medicine (Baltimore) ; 100(4): e24484, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530265

RESUMEN

BACKGROUND: Ewing sarcoma (ES), the second most prevalent bone malignant tumor has no widely known prognostic biomarker. Earlier studies have suggested that chaperonin containing TCP1 complex 6A (CCT6A), which encodes a molecular protein chaperone, is involved in the pathogenesis of many cancers. However, there are no known reports providing clear evidence of its role in ES pathogenesis. METHODS: We performed a bioinformatic analysis of 32 ES specimens from the GSE17618 dataset concentrating on the differences in gene expression, OS, event-free survival (EFS) in the different subgroups. Immunohistochemical studies were also performed to identify the expression levels of selected genes in ES and immediate paracancerous tissues. RESULTS: After 3 screenings, CCT6A was identified to be highly correlated with ES prognosis. Our survival analysis revealed a low overall survival (OS) for high CCT6A expression (P-value = .024). Our Cox regression analysis identified CCT6A expression, lEFS, and age were strongly associated with prognosis of ES. Our multivariate Cox regression analysis shows that CCT6A (P-value = .015), age (P-value = .026), and EFS (P-value = .002) were independent poor prognostic biomarkers. Our immunohistochemical analysis showed that the expression levels of CCT6A were significantly higher in ES tissues compared to the paracancerous tissues. CONCLUSION: From the results of our study, we identified the expression levels of CCT6A to be strongly associated with prognosis of ES. Thus, the expression levels of the CCT6A gene could serve as a biomarker for the prediction of ES prognosis.


Asunto(s)
Neoplasias Óseas/genética , Chaperonina con TCP-1/metabolismo , Sarcoma de Ewing/genética , Adolescente , Factores de Edad , Biomarcadores de Tumor/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Bases de Datos Genéticas , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Adulto Joven
13.
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
14.
Nat Commun ; 12(1): 498, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33479225

RESUMEN

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.


Asunto(s)
Algoritmos , Neoplasias Óseas/genética , Metilación de ADN , Aprendizaje Automático , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias Óseas/clasificación , Neoplasias Óseas/diagnóstico , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Humanos , Internet , Reproducibilidad de los Resultados , Sarcoma/clasificación , Sarcoma/diagnóstico , Sensibilidad y Especificidad , Neoplasias de los Tejidos Blandos/clasificación , Neoplasias de los Tejidos Blandos/diagnóstico
15.
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
17.
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
18.
Gene ; 775: 145419, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33444686

RESUMEN

BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women and its metastases results in poor survival rates in patients. The ability to alter metabolism is a key attribute cancer cells use to survive within different metastatic microenvironments and cause organ failure. We hypothesized that evaluation of metabolic alterations within tumor cells could provide a better understanding of cancer metastasis. Therefore, to investigate underlying metabolic alterations during metastases, we utilized human MDA-MB-231 and mouse 4T1 models that closely mimic human breast cancer metastasis. METHODS: The glycolysis and glutamine pathway-related changes were examined in bone metastatic cells by XF-24 extracellular flux analyzer and western blotting. The expression levels of genes related to metabolism were examined by PCR arrays. RESULTS: The MDA-MB-231 cells isolated after bone metastases showed reduced glucose uptake and glycolysis compared to parental cells, suggesting that these cells could alter metabolic requirements for survival. To understand these metabolic changes, we investigated glutamine, a common and naturally occurring non-essential amino acid. Interestingly, in reduced glucose conditions both cell lines showed dependence on glutamine for cell survival, and with glutamine withdrawal significantly increasing apoptotic cell death. Glutamine was also critical for normal cell proliferation even in the presence of high glucose concentrations. To further understand this metabolic switch in metastatic cells, we examined the genes related to metabolism and identified a more than seven-fold downregulation of protein kinase C zeta (PKC-ζ) expression levels in bone-derived MDA-MB-231 cells compared to the parental population. The PKC-ζ levels were also significantly reduced in metastatic 4T1 cells compared to non-metastatic MT1A2 cells. Since PKC-ζ deficiency promotes glutamine utilization via the serine biosynthesis pathway, we examined glutamine metabolism. The ectopic expression of PKC-ζ inhibited glutamine conversion to glutamate, while mutant PKC-ζ reversed this effect. Furthermore, the gene expression levels of enzymes involved in serine biosynthesis, phosphoserine phosphatase (PSPH), phosphoserine aminotransferase (PSAT1), and phosphoglycerate dehydrogenase (PHGDH) showed upregulation following glucose deprivation with PKC-ζ deficiency. The PHGDH upregulation was inhibited by ectopically expressing wild type but not mutated PKC-ζ in glucose-deprived conditions. CONCLUSIONS: Our results support the upregulation of serine biosynthesis pathway genes and downregulation of PKC-ζ as potential metabolic alterations for bone metastatic breast cancer cells.


Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Glutamina/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Animales , Vías Biosintéticas , Neoplasias Óseas/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Ratones , Modelos Biológicos , Microambiente Tumoral
19.
Zhonghua Bing Li Xue Za Zhi ; 50(1): 44-48, 2021 Jan 08.
Artículo en Chino | MEDLINE | ID: mdl-33396986

RESUMEN

Objective: To investigate the clinicopathologic features, differential diagnosis, immunohistochemical profiles and molecular characteristics of primary extraskeletal osteosarcoma (ESOS). Methods: Ten cases of ESOS diagnosed and treated in Fujian Provincial Hospital, Fuzhou, China from January 2003 to January 2019 were collected and subjected to immunohistochemical staining and molecular analyses. The patients were followed up by telephone interview. Relative literature was also reviewed to assess the characteristics of this tumor. Results: The ten cases occurred in 3 women and 7 men, aged from 36 to 85 years (median, 60 years). The sizes of these tumors ranged from 5.5 to 17.5 cm (median, 11.0 cm). Histologically, at low magnification, the tumors were nodular, leafy and lobulated. They were composed of spindle cells, neoplastic osteoid cells, and cartilage tissues, with unequally-proportional mixture of these components. The three components intermingled with each other. Immunohistochemistry profiling showed that the tumor cells were positive for SATB2 (9/9), while α-SMA (4/10) and EMA (1/10) stains were focally positive. Ki-67 proliferation index was 10%‒50%. Desmin, CD68, S-100 protein, SOX10, HMB45, CD117, DOG1, CD34, CKpan, GATA3 and PAX8 stains were negative. MDM2/CDK4 gene amplification signals were not detected in the 6 cases (0/6), which were subjected to the FISH. The SSX18 break-apart signal and the C-KIT and PDGFR-α mutations were not detected (0/5 and 0/3, respectively). Conclusions: Primary ESOS is an extra-osseous osteogenic tumor. The diagnosis is mainly dependent on clinical, radiological and pathological characteristics. Immunohistochemistry and molecular profiling are helpful for making the correct diagnosis.


Asunto(s)
Neoplasias Óseas , Proteínas de Unión a la Región de Fijación a la Matriz , Neoplasias de los Tejidos Conjuntivo y Blando , Osteosarcoma , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , China , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Factores de Transcripción
20.
Methods Mol Biol ; 2226: 15-25, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33326090

RESUMEN

Western blot is an experimental method used to analyze protein expression. In Ewing sarcoma, as in many other diseases, Western blot provides information about the level of protein expression in different cell conditions, in comparison with other tissues or upon induced molecular changes. Based on the specific pattern of protein expression of the tissue, as well as on the characteristics of the protein of interest, the antibodies and protocol of Western blot may be modified according to different specifications. Here we describe some of these peculiarities in frame of Ewing sarcoma field.


Asunto(s)
Biomarcadores de Tumor , Western Blotting , Neoplasias Óseas/metabolismo , Sarcoma de Ewing/metabolismo , Western Blotting/métodos , Neoplasias Óseas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Sarcoma de Ewing/genética
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