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1.
Oncogene ; 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32372060

RESUMO

Hepatocellular carcinoma (HCC) metastasis is largely responsible for HCC-associated recurrence and mortality. We aimed to identify metastasis-related long non-coding RNAs (lncRNAs) to understand the molecular mechanism of HCC metastasis. We first identified that miR-1258 was downregulated in HCC tissues both in The Cancer Genome Atlas (TCGA) and Sun Yat-sen University Cancer Center (SYSUCC) dataset. MiR-1258 expression negatively correlated with recurrence-free survival and overall survival of HCC patients. MiR-1258 overexpression inhibited migration and invasion of HCC cells both in vitro and in vivo, whereas miR-1258 downregulation promoted cell metastasis. Luciferase assays verified direct binding of miR-1258 to Smad2 and Smad3, thereby attenuating TGF-ß/Smad signaling. We further established that lncRNA LINC01278 was a negative regulator of miR-1258. In vivo and in vitro assays demonstrated that LINC01278-mediated HCC metastasis was dependent on miR-1258 expression. Furthermore, miR-1258 downregulation in turn increased LINC01278 expression. We also observed that TCF-4 could bind to the LINC01278 promoter site. In addition, LINC01278 downregulation decreased migration and invasion of HCC cells induced by ß-catenin and TGF-ß1 both in vitro and in vivo. We uncovered a novel mechanism for ß-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 feedback loop activation in HCC metastasis, and the study indicated that LINC01278 could serve as a therapeutic target for HCC metastasis.

2.
Ann Hematol ; 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32285160

RESUMO

To assess the survival outcomes and adverse events (AEs) of high-intermediate- or high-risk patients with diffuse large B cell lymphoma (DLBCL) who underwent conventional chemotherapy plus rituximab with or without first-line autologous stem cell transplantation (ASCT). Related studies published on Medline, Embase, Cochrane Library, and Web of science were searched, comprising both retrospective and randomized clinical trials (RCTs). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The meta-analysis was performed using the software RevMan v5.3. Four RCTs and six retrospective trials with a total of 1811 patients were identified. Pooled data indicated that conventional chemotherapy plus rituximab followed by ASCT as the first-line therapy contributed to better PFS (HR = 0.73, 95% CI 0.62-0.86, p = 0.0002) but did not significantly improve OS (HR = 0.74, 95% CI 0.55-1.01, p = 0.06) of high-intermediate/high-risk patients. Subgroup analyses of patients with complete remission after induction chemotherapy may benefit from the upfront ASCT (OS, HR = 0.48, 95% CI 0.28-0.82, p = 0.008). The incidences of grade ≥ 3 hematological and non-hematological AEs occurred more frequently in the transplantation group. High-intermediate or high-risk untreated patients with DLBCL only achieved short-term survival benefit with the upfront ASCT.

3.
Leukemia ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080345

RESUMO

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565-6.628; p < 0.001), disease-free survival (DFS: HR 3.148, 95% CI 1.857-5.339; p < 0.001), and overall survival (OS: HR 3.790, 95% CI 2.237-6.423; p < 0.001) compared with low-risk patients. The prognostic accuracy of the classifier was validated in the internal testing (n = 84) and independent validation cohorts (n = 360). A prognostic nomogram consisting of five independent variables including the classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement, and NOTCH1/FBXW7 status showed significantly greater prognostic accuracy than each single variable alone. The addition of a five-miRNA-based signature further enhanced the accuracy of this nomogram. Furthermore, patients with a nomogram score ≥154.2 significantly benefited from the BFM protocol. In conclusion, our nomogram comprising the 11-gene-based classifier may make contributions to individual prognosis prediction and treatment decision-making.

4.
Theranostics ; 9(7): 1965-1979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037150

RESUMO

Rationale: The incidence of hepatocellular carcinoma is rising worldwide. It is predicted that nearly half of the early-stage hepatocellular carcinoma (E-HCC) patients will develop recurrence. Dysregulated pH, a hallmark of E-HCC, is correlated with poor prognosis. The acidic microenvironment has been shown to promote the release of exosomes, the membrane vesicles recognized as intercellular communicators associated with tumor progression, recurrence, and metastasis. We, therefore, aimed to identify exosomes induced by acidic microenvironment that may regulate E-HCC progression and to explore their mechanisms and clinical significance in E-HCCs. Methods: miRNA microarray analysis and LASSO logistic statistic model were used to identify the main functional exosomal miRNAs. Invasion and scratch assays were performed to examine the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were employed to detect the epithelial-to-mesenchymal transition (EMT) in HCC cells. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of HIF-1α and HIF-2α to promoter regions of miR-21 and miR-10b. Results: The acidic microenvironment in HCC was correlated with poor prognosis of patients. Exosomes from HCC cells cultured in the acidic medium could promote cell proliferation, migration, and invasion of recipient HCC cells. We identified miR-21 and miR-10b as the most important functional miRNAs in acidic HCC-derived exosomes. Also, the acidic microenvironment triggered the activation of HIF-1α and HIF-2α and stimulated exosomal miR-21 and miR-10b expression substantially promoting HCC cell proliferation, migration, and invasion both in vivo and in vitro. In E-HCC patients, serum exosomal miR-21 and miR-10b levels were associated with advanced tumor stage and HIF-1α and HIF-2α expression and were independent prognostic factors for disease-free survival of E-HCC patients. Most importantly, we developed a nano-drug to target exosomal miR-21 and/or miR-10b and examined its therapeutic effects against HCC in vivo. Conclusion: Our findings suggested that the exosomal miR-21 and miR-10b induced by acidic microenvironment in HCC promote cancer cell proliferation and metastasis and may serve as prognostic molecular markers and therapeutic targets for HCC.

5.
Leukemia ; 33(10): 2454-2465, 2019 10.
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.


Assuntos
MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão/métodos
6.
Oncogene ; 37(20): 2660-2675, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29483646

RESUMO

Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.


Assuntos
Neoplasias Pulmonares/patologia , MicroRNAs/genética , NADPH Oxidases/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados Genéticas , Transição Epitelial-Mesenquimal , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Camundongos , NF-kappa B/metabolismo , Transplante de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais , Neoplasias Gástricas/genética , Análise de Sobrevida
7.
Oncotarget ; 8(40): 67241-67253, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28978030

RESUMO

Pin2/TRF1-interacting telomere inhibitor 1 (PinX1) was originally identified as a telomerase inhibitor, involved in maintaining telomerase activity, telomere length, and chromosomal stability. However, research has shown that PinX1 can have opposing molecular status in its expression patterns in several other tumor types. We thus investigated the genetic profile and biological implication of PinX1 in several human cancers using the cBioportal database. Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma. We found few instances of PinX1 gene mutations and 3D structural analysis demonstrated that these mutation sites were always located within telomerase inhibitor domains. Furthermore, our analysis of several human cancers from the cBioportal database revealed more frequent PinX1 homozygous depletion and PinX1 heterozygous deficiency, but both more infrequent PinX1 gain and rare instances of PinX1 amplification. The status of PinX1 genetic alterations was correlated with prognosis and may be tumor-type specific. As such, its biological function in tumorigenesis and later prognosis is complicated and may involve co-worked with NEIL2, R3HCC1, POLR3D, GTF2E2, and INTS10. In addition, we observed that PinX1 interacts with TERT, DKC1, PTGES3, and HSP90AA1. PinX1 mRNA expression was decreased in most selected cancer tissues, which could promote tumor growth and enhance tumorigenicity. Collectively, our data reveal PinX1 expression patterns and potential mechanisms in various human cancers. Further work will be needed to comprehensively examine its role in tumor genesis and progression.

8.
Mol Cancer ; 16(1): 74, 2017 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-28372542

RESUMO

BACKGROUND: The telomerase/telomere interacting protein PinX1 has been suggested as a tumor suppressor. However, the clinical and biological significance of PinX1 in human non-small cell lung cancer (NSCLC) is unclear. METHODS: PinX1 gene/expression pattern and its association with NSCLC patient survival were analyzed in cBioportal Web resource and two cohorts of NSCLC samples. A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on NSCLC cells proliferation and underlying mechanisms. RESULTS: More frequency of gene PinX1 homozygous deletion and heterozygote deficiency was first retrieved from cBioportal Web resource. Low expression of PinX1 correlated with smoking condition, histological type, T stage, N stage, M stage and TNM stage, and was an independent predictor for overall survival in a learning cohort (n = 93) and a validation cohort (n = 51) of NSCLC patients. Furthermore, knockdown of PinX1 dramatically accelerated NSCLC cell proliferation and G1/S transition, whereas ectopic overexpression of PinX1 substantially inhibited cell viability and cell cycle transition in vitro and in vivo. p15/cyclin D1 pathway and BMP5 might contribute to PinX1-associated cell proliferation and cell cycle transition. CONCLUSION: The cost-effective expression of PinX1 could constitute a novel molecular predictor/marker for NSCLC management.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Animais , Biomarcadores Tumorais , Proteína Morfogenética Óssea 5/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados de Ácidos Nucleicos , Modelos Animais de Doenças , Feminino , Deleção de Genes , Inativação Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Sci Rep ; 5: 17336, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26670461

RESUMO

Insulin-like growth factor binding protein-3 (IGFBP-3) plays an essential role in radiosensitivity of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism is not completely understood. Here, we observed that IGFBP-3 had favorable impact on the tumorigenicity of ESCC cells in nude mice by using an in vivo imaging system (IVIS) to monitor tumor growth treated with ionizing radiation (IR). Downregulation of IGFBP-3 expression enhanced tumor growth, inhibited anti-proliferative and apoptotic activity and result in IR resistance in vivo. Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation. Downregulation of P21 and P27, and upregulation of p-P27 (phospho-Thr187), cyclin-dependent kinase 2 (CDK2), and cyclin E1 might contribute to the G0/G1 to S phase transition promoted by IGFBP-3. Our results suggest that Smad3-P27/P21-cyclin E1/CDK2-phosphorylated retinoblastoma protein pathways might be involved in this IGFBP-3 mediated radiosensitivity transition in ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Tolerância a Radiação/genética , Animais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Modelos Animais de Doenças , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Modelos Biológicos , Fosforilação , Prognóstico , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Tumour Biol ; 36(6): 4405-15, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25596704

RESUMO

The homeobox gene NKX6.1 was recently identified in cervical tumors. This study was designed to explore the clinical and prognostic significance of NKX6.1 further in patients with primary hepatocellular carcinoma (HCC). The expression levels of NKX6.1 were examined using real-time PCR, Western blotting, and immunohistochemistry in HCC cell lines and HCC tissues. The invasion capability of cell lines following silencing or overexpression of NKX6.1 was investigated by Transwell assay. Cells proliferation was tested by MTT assays. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to NKX6.1 expression. Correlation between NKX6.1 immunohistochemical staining, clinicopathologic parameters, and follow-up data of HCC patients was analyzed statistically. NKX6.1 expression was higher in HCC tissues compared to the adjacent noncancerous tissue. NKX6.1 overexpression was significantly correlated with tumor size, tumor differentiation, clinical stage, metastasis, and relapse. Kaplan-Meier analysis revealed that NKX6.1 overexpression was related to unfavorable 5-year disease-free survival and overall survival. Importantly, multivariate analysis indicated that NKX6.1 overexpression was an independent unfavorable marker for overall survival. Moreover, a significant relationship was observed between NKX6.1 and EMT marker expression levels, and NKX6.1 knockdown inhibited cell invasion, and overexpression of NKX6.1 promotes cell proliferation in vitro. NKX6.1 is upregulated in HCC and is a reliable prognostic marker for patients with HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Proteínas de Homeodomínio/genética , Neoplasias Hepáticas/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Proteínas de Homeodomínio/biossíntese , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Recidiva Local de Neoplasia/patologia , Prognóstico
11.
Hepatol Res ; 45(2): 228-37, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24716715

RESUMO

AIM: The homeobox gene Barx2 was recently identified as a regulator of ovarian and breast cancer; however, the expression level of BARX2 and its significance in hepatocellular carcinoma (HCC) remain unknown. METHODS: Protein and mRNA expression levels of Barx2 were examined using Western blotting and real-time PCR respectively, in paired HCC tissue and matched adjacent non-cancerous tissue from 12 patients. The expression levels of epithelial-mesenchymal transition (EMT) markers were also detected in relation to BARX2 expression. Lastly, immunohistochemistry for BARX2 was also performed on a tissue microarray containing 231 HCC tissue samples. RESULTS: We observed that BARX2 expression was lower in HCC tissues compared to matching adjacent non-cancerous tissue. The low expression level of BARX2 was significantly correlated with metrics of tumor size, tumor differentiation, clinical stage, metastasis and relapse. Furthermore, the patients with low BARX2 expression had adverse survival outcomes. Importantly, multivariate Cox regression analysis revealed that low BARX2 expression was an independent marker for lower overall survival (P = 0.007). Moreover, a significant negative relationship was observed between the expression of BARX2 and markers of EMT. CONCLUSION: These findings provide evidence that the low expression level of BARX2 in HCC is significantly correlated with tumor metastasis, and that BARX2 may be an independent prognostic biomarker for patients with HCC.

12.
BMC Cancer ; 14: 583, 2014 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-25109220

RESUMO

BACKGROUND: Hemostatic alterations occur during the development of cancer. Plasma D-dimer is a hypercoagulability and fibrinolytic system marker that is increased in patients with various solid tumours. The aim of this study was to evaluate the hemostatic status of nasopharyngeal carcinoma (NPC) patients by assessing plasma D-dimer levels to investigate its value as a prognostic marker. METHODS: We retrospectively analysed 717 patients with nasopharyngeal carcinoma, and we applied Cox regression and log-rank tests to assess the association of D-dimer levels with disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS). D-dimer levels were measured using a quantitative D-dimer latex agglutination assay. RESULTS: Using the 3rd quartile values (0.8 µg/L) as the optimal cut-offs, we found that patients with high D-dimer levels have a shorter 3-year DFS, (79%, 95%CI (73.1-84.9)) vs. (69%, 95%CI (59.2-78.8)), DMFS (87%, 95%CI (83.1-90.9)) vs. (77%, 95%CI (69.2-84.8)), and overall survival (82%, 95%CI (76.1-87.9)) vs. (76%, 95%CI (66.2-85.8)). Multivariate analysis revealed that pre-treatment D-dimer levels and EBV DNA were significant independent factors for DFS, DMFS, and OS in NPC patients. Subgroup analyses indicated that the plasma D-dimer levels could effectively stratify patient prognosis for early cancer, advanced stage cancer, and patients with EBV DNA ≥4000 copies/ml. CONCLUSIONS: High D-dimer levels were associated with poor disease-free survival, distant metastasis-free survival, overall survival, and increased risk of mortality in NPC patients. Prospective trials are required to assess the prognostic value of D-dimer levels.


Assuntos
Quimiorradioterapia , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Adulto , Idoso , Carcinoma , DNA Viral/sangue , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/mortalidade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do Tratamento
13.
Cancer Lett ; 353(1): 104-14, 2014 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-25045845

RESUMO

Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Fuso Acromático/efeitos dos fármacos , Telômero/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HeLa , Humanos , Cinetocoros/efeitos dos fármacos , Cinetocoros/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Interferência de RNA , Fuso Acromático/metabolismo , Análise de Sobrevida , Telomerase/metabolismo , Telômero/metabolismo , Fatores de Tempo , Transfecção , Resultado do Tratamento , Moduladores de Tubulina/administração & dosagem , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Oncotarget ; 5(16): 6716-33, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25071013

RESUMO

UNLABELLED: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways. CONCLUSION: This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Metaloproteinase 2 da Matriz/biossíntese , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/terapia , Fatores de Iniciação de Peptídeos/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Mol Cancer ; 12(1): 148, 2013 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-24268029

RESUMO

BACKGROUND: PIN2/TRF1-interacting telomerase inhibitor1 (PinX1) was recently suggested as a putative tumor suppressor in several types of human cancer, based on its binding to and inhibition of telomerase. Moreover, loss of PinX1 has been detected in many human malignancies. However, the possible involvement of PinX1 and its clinical/prognostic significance in urothelial carcinoma of the bladder (UCB) are unclear. METHODS: The PinX1 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) in UCB tissues and adjacent normal urothelial bladder epithelial tissues. PinX1 was overexpressed and silenced in UCB cell lines to determine its role in tumorigenesis, development of UCB, and the possible mechanism. RESULTS: PinX1 expression in UCB was significantly down-regulated at both mRNA and protein level as compared with that in normal urothelial bladder epithelial tissues. PinX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index (Ki-67), and poor survival (P < 0.05). Moreover, overexpression of PinX1 in UCB cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing PinX1 dramatically enhanced cell proliferation. Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway. CONCLUSIONS: These findings suggest that down-regulation of PinX1 play an important role in the tumorigenesis and development of UCB and that the expression of PinX1 as detected by IHC is an independent molecular marker in patients with UCB.


Assuntos
Carcinoma de Células de Transição/enzimologia , Ciclina D1/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Telomerase/metabolismo , Proteínas Supressoras de Tumor/fisiologia , Neoplasias da Bexiga Urinária/enzimologia , Animais , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise Multivariada , Transplante de Neoplasias , Modelos de Riscos Proporcionais , Transdução de Sinais , Homeostase do Telômero , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
16.
Zhonghua Yi Xue Za Zhi ; 93(10): 751-5, 2013 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-23755812

RESUMO

OBJECTIVE: To explore the prevalence and clinical characteristics of isocitrate dehydrogenase (IDH)1 R132 and IDH2 R140/R172 gene mutations in acute myeloid leukemia (AML) patients. METHODS: Polymerase chain reaction (PCR) and direct sequencing were used to sequence exon 4 of IDH gene in 570 AML patients from 2005 to 2011. RESULTS: In a cohort of 570 patients, AML IDH gene mutation was found in 90 (15.79%) patients. IDH1 and IDH2 mutations were detected in 27 (4.74%) patients and 63 (11.05%) patients respectively. None of them had the combined mutations of IDH1 and IDH2. The highest frequency of IDH mutations was found in AML M1 (according to the FAB scheme) compared with all other subtypes (P < 0.01). The median age was 53 years in mutated group versus 40 years in wild-type group (P = 0.010). Mutated and wild-type groups had no significant difference in gender, white blood cell count at diagnosis, hemoglobin count and bone marrow blast percentage, excepting for blood platelets level (median 52×10(9)/L vs 31×10(9)/L, P < 0.01). IDH gene mutations were associated with cytogenetically normal (CN)-AML, NPM1 mutations and particularly with the genotype of mutated NPM1 without FLT3-ITD. IDH gene mutations had no significant correlation with WT1, FLT3-TKD and MLL-PTD mutations. IDH mutated patients had a lower complete remission rate than unmutated in non-M3 patients (58.1% vs 77.9%, P < 0.05). And the patients with mutant IDH gene were associated with a shorter overall survival (28.4% vs 51.3%, P < 0.01). CONCLUSION: IDH gene mutations are more prevalent in elder AML patients and it may constitute a molecular marker for a poor prognosis in AML.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 21(1): 39-44, 2013 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-23484688

RESUMO

This study was aimed to explore whether multiple common gene mutations of leukemia synergistically involved in acute promyelocytic leukemia (APL) pathogenesis, and to investigate their relevance to clinical features, cytogenetics and molecular risk stratification. 84 specimens of admitted de novo APL patients from February 2005 to October 2010 were collected, the gene mutations of bone marrow mononuclear cells and clinical features of mutation-positive patients were analyzed by genomic DNA-PCR. The results indicated that the prevalence of mutations was 60.7% (51/84), in which the mutations with the highest incidence were found as FLT3-ITD, reaching 27.4% (23/84). Next, there were 12 cases WT1 mutation, 9 for FLT3-TKD, 7 for TET2, 5 for N-RAS, 4 for ASXL1, 2 for EZH2 mutation and 1 positive case in MLL-PTD, IDH1 and CBL mutation respectively. No mutation was found in other JAK1, DNMT3, c-Kit, NPM1, IDH2, RUNX1 and JAK2 (V617F) common leukemia-related genes. Combined analysis with clinical data demonstrated that the patients with FLT3-ITD mutation displayed higher white blood cell counts, while the patients with N-RAS mutation showed lower platelet counts. Overall survival of these patients was obviously shorten as compared with patients with wild-type. This difference between mutant and wild-type of all above mentioned cases was statistically significant (P < 0.05). The difference between APL with simple t (15;17) and additional abnormal karyotype was not statistically significant. It is concluded that the FLT3-ITD mutation is recurrent genetic change in APL, and together with N-RAS mutation indicates poor prognosis. Additional abnormal karyotype does not associate with prognosis of APL.


Assuntos
Leucemia Promielocítica Aguda/genética , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Complexo Repressor Polycomb 2/genética , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Repressoras/genética , Sequências de Repetição em Tandem , Adulto Jovem
18.
Asian Pac J Cancer Prev ; 13(11): 5421-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23317194

RESUMO

A monosomal karyotype (MK), defined as ≥2 autosomal monosomies or a single monosomy in the presence of additional structural abnormalities, was recently identified as an independent prognostic factor conveying an extremely poor prognosis in patients with acute myeloid leukemia (AML). In the present study, after excluding patients with t(15;17), t(8;21), inv(16) and normal karyotypes, 324 AML patients with cytogenetic abnormalities were the main subject of analysis. The incidences of MK were 13% in patients aged 15 to 60 years and 18% in those between 15 and 88 years old. MK was much more prevalent among elderly patients (p<0.001) and was significantly associated with the presence of -7, -5, del(5q), abn12p, abn17p, -18 or 18q-, -20 or 20q- and CK (for all p<0.001 except for abn12p p=0.009), and +8 or +8q was less frequent in MK+ AML(p=0.007). No correlation was noted between monosomal karyotype and FAB subtype (p>0.05); MK remained significantly associated with worse overall survival among patients with complex karyotype (p=0.032); A single autosomal monosomy contributed an additional negative effect in OS of patients with structural cytogenetic abnormalities (P=0.008). This report presents the prevalence, feature and prognostic impact of MK among a large series of Chinese AML patients from a single center for the first time.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Aberrações Cromossômicas , Leucemia Mieloide Aguda/genética , Monossomia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Taxa de Sobrevida , Adulto Jovem
19.
Am J Chin Med ; 39(3): 537-50, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21598420

RESUMO

Acremoniumterricola milleretal mycelium (AMM) is one of the most precious traditional Chinese medicines. It has numerous protective effects on organs, and has been used in Chinese herb prescription to treat refractory diseases. Our preliminary studies demonstrated that AMM had hepatoprotective activity in acute liver injury. We further investigated the effects of AMM on liver fibrosis in rats induced by carbon tetrachloride (CCl(4)) and explore its possible mechanisms. The animal model was established by injection with 50% CCl(4) subcutaneously in male Sprague-Dawley rats twice a week for eight weeks. Meanwhile, AMM (175, 350 and 700 mg/kg) was administered intragastrically per day until sacrifice. We found that treatment with AMM (175, 350 and 700 mg/kg) decreased CCl(4)-induced elevation of serum transaminase activities, hyaluronic acid, laminin and procollagen type III levels, and contents of hydroxyproline in liver tissues. It also restored the decreased SOD and GSH-Px activities and inhibited the formation of lipid peroxidative products during CCl(4) treatment. Moreover, AMM (350 and 700 mg/kg) decreased the elevation of TGF-ß1 by 19.6% and 34.3%, respectively. In the pathological study, liver injury and the formation of liver fibrosis in rates treated by AMM were improved significantly. Immunoblot analysis showed that AMM (175, 350 and 700 mg/kg) inhibited Smad 2/3 phosphorylation, and elevated inhibitor Smad 7 expression. These results suggested that AMM could protect liver damage and inhibit the progression of hepatic fibrosis induced by CCl(4), and its mechanisms might be associated with its ability to scavenge free radicals, decrease the level of TGF-ß1 and block TGF-ß/Smad signaling pathway.


Assuntos
Acremonium , Antioxidantes/uso terapêutico , Produtos Biológicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Tetracloreto de Carbono , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Glutationa Peroxidase/metabolismo , Ácido Hialurônico/sangue , Hidroxiprolina/metabolismo , Laminina/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , Micélio , Fosforilação , Pró-Colágeno/sangue , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Superóxido Dismutase/metabolismo , Transaminases/sangue , Fator de Crescimento Transformador beta1/metabolismo
20.
Zhonghua Gan Zang Bing Za Zhi ; 17(9): 653-6, 2009 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-19785950

RESUMO

OBJECTIVE: To investigate the dynamic changes of a-AR, b1-AR and b2-AR expression in hepatic fibrosis. METHODS: Rat hepatic fibrosis model was established by bile duct ligation (BDL). HE and Masson staining were used to determine hepatic fibrosis levels. Immunohistochemistry was applied to detect alpha -smooth muscle actin (alpha -SMA), a marker of hepatic stellate cell (HSC) activation; Western blot and real-time RT-PCR were used to measure the dynamic changes of alpha -AR, beta(1)-AR, beta(2)-AR expression on protein and mRNA levels, respectively, during the development of hepatic fibrosis. RESULTS: (1) HE and Masson trichrome staining showed that the liver fibrosis models were established successfully. (2) At 1, 2, 3, 4 wk after BDL, alpha -SMA positive area density of the model group (10.58% +/- 1.75%, 24.14% +/- 2.02%, 29.74% +/- 2.59%, 34.28% +/- 2.01%) was significantly higher than that of the sham operation group (4.12% +/- 1.51%), P less than 0.01. (3) The expression of alpha -AR, beta(1)-AR, beta(2)-AR protein and mRNA was increased with the development of the hepatic fibrosis (P less than 0.05). (4) alpha -SMA expression was positively associated with alpha -AR, beta(1)-AR, beta(2)-AR, r values were 0.564, 0.753 and 0.606, respectively. CONCLUSION: The expression of alpha -SMA is increased dramatically during the fibrosis, and is positively associated with the expression of alpha -AR, beta(1)-AR and beta(2)-AR.


Assuntos
Actinas/metabolismo , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Experimental/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Imuno-Histoquímica , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/patologia , Cirrose Hepática Experimental/patologia , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa/genética , Receptores Adrenérgicos beta/genética , Sistema Nervoso Simpático/metabolismo , Fatores de Tempo
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