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1.
Leukemia ; 33(10): 2454-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30953029

RESUMO

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

2.
Oncol Rep ; 41(1): 235-245, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30542722

RESUMO

Tumor cells must resist anoikis to metastasize. There is a key role of angiogenesis in the growth and metastasis of tumors. However, the relationship between anoikis resistance and angiogenesis has not been well explored in human osteosarcoma. In the present study, we reported the higher expression of vascular endothelial growth factor­A (VEGF­A) in osteosarcoma cells that were resistant to anoikis than in parental osteosarcoma cells, promoting the proliferation, tube formation, and migration of human umbilical vein endothelial cells (HUVECs). Src, JNK (Jun amino­terminal kinase) and ERK (extracellular signal­regulated kinase) signaling pathway phosphorylation was activated in anoikis­resistant cells; Src inhibitor reduced the expression of VEGF­A and angiogenesis and inhibited JNK and ERK pathway activity. Overexpression of phosphorylated (p)­Src and VEGF­A was positively correlated to the metastatic potential in human osteosarcoma tissues, as quantified by immunohistochemistry. In addition, p­Src expression was directly correlated with VEGF­A expression and microvessel density in vivo. Our findings revealed that anoikis resistance in osteosarcoma cells increased the expression of VEGF­A and angiogenesis through the Src/JNK/ERK signaling pathways. Thus, Src may be a potential therapeutic alternative in osteosarcoma angiogenesis and metastasis.


Assuntos
Anoikis , Sistema de Sinalização das MAP Quinases , Neovascularização Patológica/patologia , Osteossarcoma/patologia , Quinases da Família src/metabolismo , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Criança , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Fosforilação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Quinases da Família src/antagonistas & inibidores
3.
Ann Diagn Pathol ; 37: 107-117, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30317149

RESUMO

BACKGROUND: Intestinal T-cell and NK/T- cell lymphomas are rare and aggressive. The diagnosis is quite difficult, especial in biopsy specimens. This study investigates the clinicopathological features of intestinal T-cell and NK/T-cell lymphomas to aid their differential diagnosis. METHODS: Clinical data of 27 cases were collected. Including extranodal NK/T-cell lymphoma, nasal type (ENKTCL-N), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), anaplastic large-cell lymphoma, ALK+ (ALCL, ALK+) and angioimmunoblastic T-cell lymphoma (AITL). The histologic features, immunohistochemical findings, T-cell receptor gene rearrangement results, and follow-up data were analyzed, with review of literature. RESULTS: The age of the patients (N = 27) was 15-85 years (mean, 47.5 years), and male:female ratio, 3.5:1. Abdominal pain and B symptoms were the most common symptoms. Although 85.2% of the patients were in clinical stage I-II, 59.3% died within 1 year. MEITL showed certain distinctive clinic opathological features from ENKTCL-N. Compared to lesions at other sites, there were no differences in the morphological features, immunophenotype and TCR gene rearrangement of intestinal ENKTCL-N, PTCL, NOS, ALCL, ALK+ and AITL. CONCLUSION: Intestinal T-cell and NK/T-cell lymphomas are a heterogeneous group of lymphomas. They could be classified to 5 histological subtypes in our study. ENKTCL-N and MEITL formed the majority of the tumor types. Each subtype has distinctive pathological features, but most of them have diamal prognosis.

4.
J Exp Clin Cancer Res ; 37(1): 188, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092789

RESUMO

BACKGROUND: Over the last two or three decades, the pace of development of treatments for osteosarcoma tends has been slow. Novel effective therapies for osteosarcoma are still lacking. Previously, we reported that tumor-suppressing STF cDNA 3 (TSSC3) functions as an imprinted tumor suppressor gene in osteosarcoma; however, the underlying mechanism by which TSSC3 suppresses the tumorigenesis and metastasis remain unclear. METHODS: We investigated the dynamic expression patterns of TSSC3 and autophagy-related proteins (autophagy related 5 (ATG5) and P62) in 33 human benign bone tumors and 58 osteosarcoma tissues using immunohistochemistry. We further investigated the correlations between TSSC3 and autophagy in osteosarcoma using western blotting and transmission electronic microscopy. CCK-8, Edu, and clone formation assays; wound healing and Transwell assays; PCR; immunohistochemistry; immunofluorescence; and western blotting were used to investigated the responses in TSSC3-overexpressing osteosarcoma cell lines, and in xenografts and metastasis in vivo models, with or without autophagy deficiency caused by chloroquine or ATG5 silencing. RESULTS: We found that ATG5 expression correlated positively with TSSC3 expression in human osteosarcoma tissues. We demonstrated that TSSC3 was an independent prognostic marker for overall survival in osteosarcoma, and positive ATG5 expression associated with positive TSSC3 expression suggested a favorable prognosis for patients. Then, we showed that TSSC3 overexpression enhanced autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway in osteosarcoma. Further results suggested autophagy contributed to TSSC3-induced suppression of tumorigenesis and metastasis in osteosarcoma in vitro and in vivo models. CONCLUSIONS: Our findings highlighted, for the first time, the importance of autophagy as an underlying mechanism in TSSC3-induced antitumor effects in osteosarcoma. We also revealed that TSSC3-associated positive ATG5 expression might be a potential predictor of favorable prognosis in patients with osteosarcoma.

5.
Oncotarget ; 8(49): 85628-85641, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29156746

RESUMO

Osteosarcoma is the most common type of bone cancer, and the second leading cause of cancer-related death in children and young adults. Osteosarcoma stem cells are essential for osteosarcoma initiation, metastasis, chemoresistance and recurrence. In the present study, we report that: 1) higher TSSC3 expression indicates a better prognosis for osteosarcoma patients, and; 2) overexpression of TSSC3 significantly decreases sphere-forming capacity, tumor initiation, stemness-related surface markers and Nanog expression in osteosarcoma cells. We also discovered that higher Nanog expression correlates to a worse prognosis for osteosarcoma patients, and overexpression of Nanog increases the stem-related phenotype in osteosarcoma cells. Knockdown of Nanog suppresses these phenotypes. Inhibition of Nanog expression and self-renewal of osteosarcoma cells by TSSC3 overexpression appears to be mediated through inactivation of the Src/Akt pathway. In the clinical setting, expression of TSSC3, p-Src and Nanog is associated with recurrence, metastasis and surgical intervention. Lower TSSC3 expression, higher Nanog expression or higher p-Src expression indicate a poor prognosis for osteosarcoma patients. Overall, our study demonstrates that TSSC3 inhibits the stem-like phenotype and Nanog expression by inactivation of the Src/Akt pathway; this emphasizes the importance of Nanog in osteosarcoma stem cells.

6.
Cell Death Dis ; 7(12): e2572, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-28032865

RESUMO

Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anoikis , Proteínas do Citoesqueleto/metabolismo , Neoplasias Pulmonares/secundário , Proteínas Nucleares/metabolismo , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Proteínas do Citoesqueleto/química , Regulação para Baixo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos SCID , Mitocôndrias/metabolismo , Modelos Biológicos , Proteínas Nucleares/química , Osteossarcoma/enzimologia , Fenótipo , Ligação Proteica , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Transcrição Genética , Adulto Jovem
7.
Am J Cancer Res ; 6(10): 2252-2262, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27822415

RESUMO

The secreted axonal guidance molecular, Semaphorin-3F (SEMA3F), is widely expressed outside the central nervous system and inhibits tumor growth and metastasis. However, the role of SEMA3F expression in the osteosarcoma prognosis has not been elaborated. This study aimed to evaluate SEMA3F expression level in osteosarcoma and assess its prognostic value for patients. SEMA3F protein expression was detected by immunohistochemistry (IHC) in 112 cases of osteosarcoma. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of SEMA3F. The results showed that the overall survival and metastasis-free survival of patients with negative SEMA3F expression were significantly shorter than patients with positive expression (both P<0.01). Multivariate Cox analysis identified SEMA3F expression as an independent prognostic factor to predict favorable overall survival and metastasis-free survival (both P<0.01). When endogenous SEMA3F expression was knocked down by siRNAs, cell proliferation, colony formation, migration and invasion in osteosarcoma cell lines were obviously promoted. Meanwhile, SEMA3F knockdown decreased E-cadherin expression but increased the expression of N-cadherin and ß-Catenin, which indicated that SEMA3F could inhibit epithelial-mesenchymal transition (EMT). Mechanically, knockdown of SEMA3F inhibited GSK-3ß protein expression and promoted the expression of ß-Catenin and c-myc proteins. GSK-3ß is a key upstream suppressor of ß-Catenin and c-myc expression is an indicator of Wnt/ß-Catenin activity. Therefore, these results suggest that down-regulated SEMA3F may promote EMT, migration, invasion and metastasis of osteosarcoma via activating Wnt/ß-Catenin signaling. In conclusion, SEMA3F is downregulated and associated with prognosis of patients, indicating that SEMA3F may be a potential prognostic biomarker and therapeutic target for osteosarcoma.

8.
Am J Cancer Res ; 6(6): 1431-40, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27429855

RESUMO

Achaetescute-like 2 (ASCL2), a basic helix-loop-helix (bHLH) transcription factor, plays an important role in the determination of neuronal precursors in the central and peripheral nervous system and involves in tumor progression. However, the role of ASCL2 expression in the osteosarcoma prognosis has not been elaborated. This study aimed to evaluate ASCL2 expression level in osteosarcoma and assess its prognostic value for patients. ASCL2 protein expression was detected by immunohistochemistry (IHC) in 73 cases of osteosarcoma. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ASCL2. Immunohistochemistry analysis showed that the overall survival and metastasis-free survival of patients with positive ASCL2 expression were significantly shorter than patients with negative expression (both P<0.01). Multivariate Cox analysis identified ASCL2 expression as an independent prognostic factor to predict poor overall survival and metastasis-free survival (both P<0.01). Overexpression of ASCL2 expression greatly promoted cell proliferation and enhanced migration and invasion in vitro. This study indicates that increased expression of ASCL2 in primary osteosarcoma is a novel biomarker for predicting the development of metastases and poor outcomes of the patients.

9.
Cancer Lett ; 373(2): 164-73, 2016 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-26845447

RESUMO

Epithelial to mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining the invasive and metastatic behavior of cells during cancer progression. Our previous study showed that loss of expression of TSSC3 is positively associated with osteosarcoma malignancy and progression. However, whether TSSC3 mediates EMT in osteosarcoma is poorly understood. In the present study, we determined that TSSC3 downregulation induced cell migration and invasion ability and promoted mesenchymal transition of osteosarcoma cells by upregulating mesenchymal markers and inhibiting the epithelial markers. Furthermore, TSSC3 downregulation elicited a signaling cascade that included increased levels of Wnt3a and LRP5, inactivation of GSK-3ß, accumulation of nuclear ß-catenin and Snail, the augmented binding of ß-catenin to TCF-4, and accordingly increased the expression of Wnt target genes (CD44, MMP7). The gene knockdown of these signaling proteins could inhibit TSSC3 downregulation-promoted EMT, migration, and invasion in osteosarcoma. Finally, TSSC3 overexpression obviously inhibited cell migration, invasion, and repressed mesenchymal phenotypes, reducing lung metastasis through GSK-3ß activation. Collectively, TSSC3 downregulation promotes the EMT of osteosarcoma cells by regulating EMT markers via a signal transduction pathway that involves Snail, Wnt-ß-catenin/TCF, and GSK-3ß.


Assuntos
Neoplasias Ósseas/patologia , Transição Epitelial-Mesenquimal , Quinase 3 da Glicogênio Sintase/fisiologia , Proteínas Nucleares/fisiologia , Osteossarcoma/patologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , beta Catenina/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Feminino , Glicogênio Sintase Quinase 3 beta , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Invasividade Neoplásica , Fatores de Transcrição da Família Snail
10.
J Cell Mol Med ; 20(7): 1219-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26893171

RESUMO

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta-analysis of all available case-control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448-2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large-scale studies considering gene-environment interactions and functional research should be conducted to further investigate this association.


Assuntos
Predisposição Genética para Doença , Proteína da Hemocromatose/genética , Mutação/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Razão de Chances , Viés de Publicação , Fatores de Risco
11.
Cancer Lett ; 370(2): 268-74, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26571463

RESUMO

Osteosarcoma is the most common type of bone cancer, especially in children and young adults. The primary treatment for osteosarcoma is a combination of surgery and chemotherapy, however prognoses remain poor due to chemoresistance and early metastases. Osteosarcoma stem cells appear to play central roles in tumor recurrence, metastases and chemoresistance via self-renewal and differentiation. Targeting these cells may provide a novel strategy in the treatment of osteosarcoma. This review summarizes current knowledge of this rare phenotype and recent advances in understanding the functions OSCs (osteosarcoma stem cells) in osteosarcoma, with the aim of improving therapies in the future.


Assuntos
Neoplasias Ósseas/patologia , Células-Tronco Neoplásicas/fisiologia , Osteossarcoma/patologia , Pesquisa com Células-Tronco , Antígeno AC133 , Antígenos CD/análise , Neoplasias Ósseas/tratamento farmacológico , Separação Celular , Glicoproteínas/análise , Proteínas Hedgehog/fisiologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Peptídeos/análise , Proteínas Proto-Oncogênicas c-kit/análise , Receptores Notch/fisiologia , Fatores de Transcrição SOXB1/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/fisiologia
12.
Sci Rep ; 5: 12999, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26265454

RESUMO

The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3.


Assuntos
Inativação Gênica , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Complexo Repressor Polycomb 2/genética , Adulto , Apoptose/genética , Linhagem Celular Tumoral , Criança , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Adulto Jovem
13.
Tumour Biol ; 36(4): 3009-15, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25613065

RESUMO

Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.


Assuntos
Neoplasias Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/biossíntese , Proteínas de Neoplasias/biossíntese , Osteossarcoma/genética , Apoptose/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Ilhas de CpG , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Osteossarcoma/patologia
14.
Tumour Biol ; 35(12): 11819-27, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25227661

RESUMO

Methyl-CpG-binding protein 2 (MeCP2) is a DNA methylation-related gene of the methyl-CpG-binding protein family. Here, we investigated the epigenetic function of the MeCP2 in SaOS2 and U2OS cell lines, and explored the antitumor effects of the gene silencing for osteosarcoma. In this study, chromatin immunoprecipitation assay was used to detect MeCP2 binding activity with TSSC3 gene. RT-PCR and western blot assay were used to analyze the MeCP2 expression in osteosarcoma cell lines after transfection with LV-MECP2-RNAi. Transwell invasion and migration assays were used to detect the cell invasion and migration. The cell apoptosis was examined by using the flow cytometry assay. The tumor size was also assessed to determine the therapeutic effects of gene silencing. The results indicated that MeCP2 indicated the highest combining power with TSSC3 gene. LV-MECP2-RNAi could decrease MeCP2 level in tumor cells compared with the untreated cells (P < 0.05). LV-MECP2-RNAi inhibited the U2OS and SaOS2 cells invasion and migration compared with the control cells (P < 0.05). LV-MECP2-RNAi triggered the U2OS and SaOS2 cell apoptosis, and inhibited the cell proliferation significantly compared with the control cells (P < 0.05). The gene silencing of RNAi could also decreased the tumor size significantly compared with untreated cells (P < 0.05). In conclusion, silencing the MeCP2 gene could block the MeCP2 expression and inhibit the tumor cell migration, invasion, and proliferation, and decreases the tumor size by inducing the apoptosis of the tumor cells.


Assuntos
Apoptose/genética , Movimento Celular/genética , Epigênese Genética , Inativação Gênica , Proteína 2 de Ligação a Metil-CpG/genética , Osteossarcoma/genética , Linhagem Celular Tumoral , Proliferação de Células , Expressão Gênica , Humanos , Proteínas Nucleares/genética , Osteossarcoma/patologia , Interferência de RNA , Carga Tumoral
15.
Exp Mol Pathol ; 96(3): 445, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24632130
16.
J Pathol ; 234(1): 11-22, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24604164

RESUMO

Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation.


Assuntos
Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioma/patologia , Proteínas Hedgehog/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133 , Aloenxertos , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/patologia , Feminino , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas Hedgehog/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Peptídeos/genética , Peptídeos/metabolismo , Fenótipo , Transdução de Sinais , Nicho de Células-Tronco , Microambiente Tumoral
17.
Biomed Pharmacother ; 68(1): 45-50, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24268429

RESUMO

Promoter hypermethylation can lead to a loss of genetic imprinting in carcinogenesis. The mechanism for the loss of expression of the imprinted gene TSSC3 has not been investigated in cases of osteosarcoma. In this study, we treated osteosarcoma cell lines with 5-Aza-CdR, which is a widely-used DNA methyltransferase inhibitor, and found dose-dependent reduction in cell growth, conversion of cell morphology to a non-motile phenotype, and obvious increase in apoptosis. In addition, we also found that 5-Aza-CdR reactivated TSSC3 expression through demethylation of the promoter regions. These findings indicate that the TSSC3 gene is silenced through hypermethylation of the promoter regions, a mechanism commonly associated with gene silencing in cancer. Finally, we examined the role of TSSC3 in human osteosarcoma SaOS2 cells. We showed that TSSC3 overexpression suppressed SaOS2 cell growth and increased apoptosis through caspase-3 upregulation, thereby, suggesting that TSSC3 may play a pro-apoptosis role to maintain the normal balance of growth. Taken together, these observations suggest that the epigenetic regulation of TSSC3, a pro-apoptosis gene, provides valuable insights into possible osteosarcoma therapies.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Azacitidina/administração & dosagem , Azacitidina/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Caspase 3/genética , Linhagem Celular Tumoral , Metilação de DNA/genética , Decitabina , Relação Dose-Resposta a Droga , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Proteínas Nucleares/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Regiões Promotoras Genéticas/genética , Regulação para Cima/genética
18.
Neuroimmunomodulation ; 20(2): 87-98, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23257628

RESUMO

OBJECTIVE: Immune cells are key mediators of secondary damage following spinal cord injury (SCI), and dendritic cell (DC)-based vaccines have received considerable interest for treatment of SCI. We previously showed that vaccination with DCs pulsed with homogenate proteins of the spinal cord (hpDCs) promotes functional recovery from SCI in mice. However, the underlying molecular mechanisms remain unclear. Here, changes of neurotrophins, cytokines and T cells at the site of SCI in mice after vaccination with hpDCs were investigated and correlated with recovery from SCI. METHODS: hpDCs, DCs (control) or PBS (control) were injected intraperitoneally into injured mouse spinal cords. Functional recovery of the spinal cord was measured weekly using the Basso Mouse Scale (BMS) and confirmed by histological and immunohistochemical analysis. Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), interleukin-4 (IL-4) and interferon-γ (IFN-γ) levels in T cell culture supernatants and spinal cord tissues were determined by ELISA. RESULTS: Eighty-four days after immunization, the BMS score of the hpDCs group (6.92 ± 0.20) was significantly higher than those of the DCs and PBS groups (p < 0.01). Meanwhile, the injury area and number of cysts in the hpDCs group decreased significantly compared with control groups. BDNF, NT-3, IL-4 and IFN-γ levels at the injured site as well as BDNF and NT-3 levels in the supernatant of cultured T cells from the hpDCs group were significantly higher than in control groups (p < 0.05). CONCLUSION: These results reveal that vaccination with hpDCs can promote SCI repair potentially by upregulating BDNF, NT-3, IL-4 and IFN-γ at the injury site.


Assuntos
Citocinas/biossíntese , Células Dendríticas/transplante , Fatores de Crescimento Neural/biossíntese , Traumatismos da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Proteínas/imunologia , Proteínas/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/imunologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Vacinação
19.
Exp Mol Pathol ; 94(1): 285-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22542792

RESUMO

To explore the polymorphisms and mutations of mitochondrial ATPase6 gene in Chinese patients with osteosarcoma and their possible association with carcinogenesis, direct DNA sequencing method was used to detect the variants of the mitochondrial ATPase6 gene in 39 patients with osteosarcoma. We found mutations of the mitochondrial ATPase6 gene in 24/39 (61.5%) of the tested osteosarcoma samples, and identified 27 variant sites in ATPase6 coding regions. We did not detect any new polymorphisms in osteosarcoma, nor was there any association between variants and the three histopathological subtypes. These data demonstrated that mtDNA mutations within the ATPase6 gene are a frequent event in Chinese patients with osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Osteossarcoma/genética , Neoplasias Ósseas/enzimologia , DNA Mitocondrial/genética , Genes Mitocondriais , Variação Genética , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mutação , Osteossarcoma/enzimologia , Análise de Sequência de DNA
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