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1.
Front Oncol ; 10: 217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219060

RESUMO

Background: Patients with metastatic radioiodine-refractory papillary thyroid carcinoma (PTC) have limited treatment options and a poor prognosis. There is an urgent need to develop new drugs targeting PTC for clinical application. Apatinib, a novel small-molecule tyrosine kinase inhibitor (TKI), is highly selective for vascular endothelial growth factor receptor-2 (VEGFR2) and exhibits antitumor effects in a variety of solid tumors. Although apatinib has been shown to be safe and efficacious in radioiodine-refractory differentiated thyroid cancer, the mechanism underlying its antitumor effect is unclear. In this report, we explored the effects of apatinib on PTC in vitro and in vivo. Methods: VEGFR2 expression levels were evaluated by immunohistochemistry (IHC), qPCR, and western blotting (WB). The effects of apatinib on cell viability, colony formation, and migration in the Transwell assay were assessed in vitro, and its effect on tumor growth rate was assessed in vivo. In addition, the levels of proteins in signaling pathways were determined by WB. Finally, the autophagy level was assessed by WB, immunofluorescence (IF), and transmission electron microscopy. Results: We found that high VEGFR2 expression is associated with tumor size, T stage, and lymph node metastasis in patients with PTC and that apatinib inhibits PTC cell growth, promotes apoptosis, and induces cell cycle arrest through the PI3K/Akt/mTOR signaling pathway. Moreover, apatinib induces autophagy, and pharmacological inhibition of autophagy or small interfering RNA (siRNA)-mediated targeting of autophagy-associated gene 5 (ATG5) can further increase PTC cell apoptosis. Conclusion: Our data suggest that apatinib can induce apoptosis and autophagy via the PI3K/Akt/mTOR signaling pathway for the treatment of PTC and that autophagy is a potential novel target for future therapy in resistant PTC.

2.
J Exp Clin Cancer Res ; 39(1): 44, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111229

RESUMO

BACKGROUND: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. METHODS: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. RESULTS: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. CONCLUSIONS: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

3.
Int J Clin Oncol ; 25(1): 59-66, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31414270

RESUMO

BACKGROUND: The aim of this study was to evaluate the prognostic veracity for disease-specific survival (DSS) of the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system (TNM-8) compared with the seventh edition (TNM-7) in a Chinese population of patients with differentiated thyroid carcinoma (DTC) and to evaluate the impact of N1b redefinition and reclassification on prediction of survival. METHODS: A total of 569 DTC patients who underwent thyroid surgery in two Chinese hospitals were included in analysis to assess the predictive accuracy and N1b changes of TNM-8. Data from the Surveillance, Epidemiology and End Results (SEER) program were applied to validate the findings on N1b changes of TNM-8. Unadjusted DSS was calculated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to evaluate the association of stage and lymph node metastasis (LNM) status with survival. The proportion of variation explained (PVE), Akaike information criterion (AIC), and Bayesian information criterion (BIC) were evaluated to compare model performance. RESULTS: When TNM-8 was applied, 39.7% of patients were downstaged relative to TMN-7. In comparison of TNM-7 and TMN-8, the PVE was 18.68% and 22.33%, the AIC was 704.22 and 680.50, and the BIC was 702.98 and 679.24, respectively. In 569 Chinese patients with DTC, levels I-V LNM was significantly related to poorer DSS compared with N0 and level VI LNM. Among patients aged ≥ 55 years, those with levels I-V and VII LNM had significantly worse DSS than those with N0 and Level VI LNM. In the SEER dataset, patients with levels I-V and VII LNM had significantly worse DSS compared with those with N0 and Level VI LNM, especially in older patients (age ≥ 55 years). CONCLUSIONS: TNM-8 staged a significant number of Chinese patients into lower stages and improved the accuracy of predicting DSS compared with TNM-7. However, changes in lateral LNM definition and classification of TNM-8 have a significant prognostic implication for patients with DTC, especially older patients (≥ 55 years). Our data suggest that a modified TNM staging system would be more useful for predicting mortality and determining a proper treatment strategy in patients with DTC.

4.
Onco Targets Ther ; 12: 6937-6945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695409

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is the most aggressive cancer in humans with no optimal treatment strategy available. The molecular mechanisms of ATC remain unclear. The aim of this study was to investigate the prognostic value and role of BRMS1 in the progression of ATC. Methods: BRMS1 expression was examined in thyroid cell lines using Western blot analysis. Immunohistochemistry was also performed to assess BRMS1 expression in ATC and papillary thyroid cancer (PTC) tissue. Cell proliferation assays, colony formation analysis, cell migration assays, cell apoptosis analysis, and animal studies were used to examine the effects of BRMS1 expression on ATC progression. Results: The expression of BRMS1 was significantly lower in ATC than in PTC and was associated with poor prognosis in ATC patients. Downregulation of BRMS1 expression promoted the proliferation and migration of 8505C cells and decreased their expression of CX43. Over-expressed BRMS1 promoted the apoptosis and impaired the proliferation and migration of CAL-62 cells via upregulated CX43. In vivo, BRMS1 significantly promoted apoptosis and impaired cell proliferation. Conclusion: Taken together, these findings demonstrate that decreased expression of BRMS1 is a poor prognostic biomarker in ATC patients. BRMS1 significantly promoted apoptosis and impaired cell proliferation via CX43 and P53. Loss of BRMS1 expression is therefore, one of the key pathomechanisms in ATC.

5.
Cancer Manag Res ; 11: 3765-3777, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118795

RESUMO

Objective: Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH. IDH2-related research has focused on its mutation mechanism and its clinical significance, but the role of wild-type IDH2 in carcinoma remains controversial. Altered IDH2 levels have been identified in several types of carcinomas. However, the significance and expression of IDH2 in thyroid cancer remains unknown. Methods: We examined the expression of IDH2 in thyroid cancer and adjacent normal tissues using quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining analyses, and western blot analysis with frozen tissues. The relationship between IDH2 and the clinicopathological features of thyroid cancer was analyzed by IHC. Subsequently, we investigated the function of wild-type IDH2 in thyroid cancer cells in vitro. Results: We found that the mRNA expression and protein levels of IDH2 were higher in tumor than in adjacent tissues, when evaluated by qRT-PCR, western blot, and IHC analyses. Tumor size, T stage, lymph node metastasis, and TNM stage showed significant differences between the IDH2 high expression and low expression groups. Multiple logistic regression analyses indicated that tumor size and IDH2 expression were significantly correlated with the occurrence of neck LNM. Furthermore, CCK8 levels, colony formation, and invasive cell number were decreased in the sh-IDH2 groups. The upregulation of IDH2 in thyroid cancer cells showed opposite effects. Conclusion: Our results indicated that IDH2 may play an important role in the development of thyroid cancer. IDH2 can be used as a potential biomarker for diagnosis and prognosis and may be a potential therapeutic target for thyroid cancer.

6.
Cancer Biol Med ; 16(1): 121-130, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31119052

RESUMO

Objective: The purposes of this study were to identify risk factors for cervical lymph node metastasis and to examine the association between BRAF V600E status and clinical features in papillary thyroid microcarcinoma (PTMC). Methods: A total of 1,587 patients with PTMC, treated in Tianjin Medical University Cancer Institute and Hospital from January 2011 to March 2013, underwent retrospective analysis. We reviewed and analyzed factors including clinical results, pathology records, ultrasound results, and BRAF V600E status. Results: Multivariate logistic regression analyses demonstrated that gender (male) [odds ratio (OR) = 1.845, P = 0.000], age (< 45 years)(OR = 1.606,P = 0.000), tumor size (> 6 mm) (OR = 2.137,P = 0.000), bilateralism (OR = 2.011, P = 0.000) and extrathyroidal extension (OR = 1.555, P = 0.001) served as independent predictors of central lymph node metastasis (CLNM). Moreover, CLNM (OR = 29.354, P = 0.000) served as an independent predictor of lateral lymph node metastasis (LLNM). Among patients with a solitary primary tumor, those with tumor location in the lower third of the thyroid lobe or the isthmus were more likely to experience CLNM (P < 0.05). Univariate analyses indicated that CLNM, LLNM, extrathyroidal extension, and multifocality were not significantly associated with BRAF V600E mutation. Conclusions: The present study suggested that prophylactic neck dissection of the central compartment should be considered in patients with PTMC, particularly in men with tumor size greater than 6 mm, age less than 45 years, extrathyroidal extension, and tumor bilaterality. Among patients with PTMC, BRAF V600E mutation is not significantly associated with prognostic factors. For a better understanding of surgical management of PTMC and the risk factors, we recommend multicenter research and long-term follow-up.

7.
Thyroid ; 29(6): 809-823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

8.
Endocr Relat Cancer ; 26(1): 153-164, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30139768

RESUMO

There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.

9.
Sci Rep ; 6: 37052, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845389

RESUMO

Hepatocellular carcinoma (HCC) is refractory to chemotherapies, necessitating novel effective agents. The lysosome inhibitor Bafilomycin A1 (BafA1) at high concentrations displays cytotoxicity in a variety of cancers. Here we show that BafA1 at nanomolar concentrations suppresses HCC cell growth in both 2 dimensional (2D) and 3D cultures. BafA1 induced cell cycle arrest in the G1 phase and triggered Cyclin D1 turnover in HCC cells in a dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) dependent manner. Notably, BafA1 induced caspase-independent cell death in HCC cells by impairing autophagy flux as demonstrated by elevated LC3 conversion and p62/SQSTM1 levels. Moreover, genetic ablation of LC3 significantly attenuated BafA1-induced cytotoxicity of HCC cells. We further demonstrate that pharmacological down-regulation or genetic depletion of p38 MAPK decreased BafA1-induced cell death via abolishment of BafA1-induced upregulation of Puma. Notably, knockdown of Puma impaired BafA1-induced HCC cell death, and overexpression of Puma enhanced BafA1-mediated HCC cell death, suggesting a role for Puma in BafA1-mediated cytotoxicity. Interestingly, pharmacological inhibition of JNK with SP600125 enhanced BafA1-mediated cytotoxicity both in vitro and in xenografts derived from HCC cells. Taken together, our data suggest that BafA1 may offer potential as an effective therapy for HCC.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular , Caspases , Neoplasias Hepáticas , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrolídeos/farmacologia , Proteínas de Neoplasias , Animais , Autofagia/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Caspases/genética , Caspases/metabolismo , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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