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1.
Mol Genet Genomic Med ; 8(1): e1017, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31782911

RESUMO

OBJECTIVE: To investigate the expression of long-chain noncoding growth stasis specific protein 6 antisense RNA1 (lncRNA DLX6-AS1) in nasopharyngeal carcinoma (NPC) tissues and cells, and its regulatory effect on malignant phenotypes of NPC cells. METHODS: The expressions of DLX6-AS1, miR-199a-5p, and HIF-1α mRNA in NPC issues and cells were detected by qRT-PCR. The proliferation, metastasis, and invasion of cells were monitored via MTT and transwell assay. The interactions between DLX6-AS1 and miR-199a-5p, miR-199a-5p and HIF-1α were verified by luciferase activity assay. Western blot was performed to determine the regulatory effect of DLX6-AS1 and miR-199a-5p on HIF-1α protein. RESULTS: The expression of lncRNA DLX6-AS1 was up-regulated in NPC tissues and cells. The proliferation, migration, and invasion of NPC were enhanced by overexpressed DLX6-AS1 but inhibited by DLX6-AS1 knockdown. In addition, DLX6-AS1 can be used as a kind of ceRNA to regulate miR-199a-5p and, thereby modulating the expression of HIF-1α. CONCLUSION: We found that DLX6-AS1 was a cancer-promoting lncRNA to facilitate the progression of NPC, and its underlying mechanism was suppressing miR-199a-5p expression. This study can provide novel clues for the treatment of NPC.

2.
Cancer Manag Res ; 11: 10187-10193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819651

RESUMO

Purpose: Circulating tumour cells (CTCs) have been found to correlate with treatment response and prognosis in some cancers; however, such correlations have not been reported in nasopharyngeal carcinoma (NPC). We aimed to determine the relationship between CTCs and the treatment response in NPC. Patients and methods: In this prospective study, we ascertained the karyotype of CTCs and identified a possible correlation between karyotype and treatment response in locally advanced NPC (LANPC). We prospectively collected peripheral blood from LANPC patients. CTCs were measured by negative enrichment with immunofluorescence in situ hybridization (imFISH) and a centromere of chromosome 8 (CEP8) probe. Chromosome 8 was karyotyped in CTCs, which were identified as triploid, tetraploid or multiploid. Patients were then treated with platinum-based induction chemotherapy followed by concurrent chemoradiotherapy. CTCs were measured before and after treatment. Results: We detected CTCs in 27 of 50 (54%) patients, which served as a baseline value. The results were independent of age, smoking history and NPC clinical stage. All of the 27 evaluable enrolled patients with detectable CTCs showed decreases in both total CTCs and CTCs of different ploidies after treatment (P<0.05). Reductions in CTCs were significantly more common in patients with a complete response (CR) than in those with a partial response (PR) (P<0.05). The presence of fewer tetraploid CTCs before treatment had a positive predictive value for a CR to chemoradiotherapy (P<0.05). CTC-positive patients had a shorter PFS after treatment (P=0.03). Conclusion: The decrease in CTCs was correlated with therapeutic efficacy in patients with LANPC, and the presence of tetraploid CTCs before treatment is a potential predictive factor for clinical outcomes.

3.
Mol Med Rep ; 20(5): 4073-4080, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485655

RESUMO

Colorectal cancer (CRC) currently leads to many deaths worldwide. The regulatory mechanism, however, remains largely unclear. In the present study, bioinformatics methods were used to identify genes associated with CRC prognosis and to detect the molecular signals regulating the cell cycle in two CRC cell lines. It was revealed that BNIPL­2 expression was higher in CRC tissues than in adjacent tissue samples. Upregulation of BNIPL­2 was correlated with poor prognosis and the adverse malignant stages T and M. BNIPL­2 was also associated with signaling pathways involved in cancer cell growth. BNIPL­2 overexpression promoted cell proliferation and increased the proportion of cells in the G2/M phase. Knockdown of BNIPL­2 inhibited cell proliferation. CD44 was regulated by BNIPL­2 and promoted cell proliferation. Downregulation of CD44 suppressed cell proliferation and rescued the cell proliferation promoted by BNIPL­2. Overexpression of CD44 restored the cell proliferation suppressed by BNIPL­2 knockdown. The present study not only suggested that BNIPL­2 may be a potential biomarker of CRC but also indicated that BNIPL­2 regulates CRC cancer proliferation via CD44, which could be a diagnostic and clinical treatment target.

4.
Front Immunol ; 10: 1101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164888

RESUMO

Vascular smooth muscle cells (VSMCs) constitute the major cells in the media layer of arteries, and are critical to maintain the integrity of the arterial wall. They participate in arterial wall remodeling, and play important roles in atherosclerosis throughout all stages of the disease. Studies demonstrate that VSMCs can adopt numerous phenotypes depending on inputs from endothelial cells (ECs) of the intima, resident cells of the adventitia, circulating immune cells, hormones, and plasma lipoproteins. This plasticity allows them to perform multiple tasks in physiology and disease. In this minireview, we focus on a previously underappreciated activity of VSMCs, i.e., their impact on atherosclerosis immunity via formation of artery tertiary lymphoid organs (ATLOs).

5.
Gene ; 707: 44-52, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30898716

RESUMO

Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially nasopharyngeal carcinoma (NPC). In present study, we aims to investigate the role and mechanism of LINC00520 in the NPC carcinogenesis. Results indicated that LINC00520 was significantly increasing in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00520 indicated the poor prognosis of NPC patients. Silence of LINC00520 was able to repress NPC cell growth in vitro while overexpression of LINC00520 inversed this process. Moreover, in vivo tumor xenografts were establishing using CNE-1/SUNE-1 cells to investigate the function of LINC00520 in NPC tumorigenesis. Rescue assay was conducting to further confirm that LINC00520 contributed to NPC progression by regulating miR-26b-3p/ubiquitin-specific protease 39 (USP39) signal pathway. Taken together, our study discovered the oncogenic role of LINC00520 in clinical specimens and cellular experiments, showing the potential LINC00520/miR-26b-3p/USP39 pathway. This results and findings provide a novel insight for NPC tumorigenesis.


Assuntos
MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Proteases Específicas de Ubiquitina/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transplante de Neoplasias , Prognóstico , Proteases Específicas de Ubiquitina/metabolismo , Regulação para Cima
6.
Nat Med ; 25(3): 529, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30718908

RESUMO

In the version of this article originally published, a sentence was erroneously included in the author contributions, and information regarding second shared authorship was missing from the author contributions. The following should not have been included in the author contributions: "C.W. and A.J.R.H. supervised the work presented in Figs. 1, 2, 5, 6; P.Z. and C.S. supervised the work presented in Figs. 3, 4." Additionally, this sentence should have appeared at the beginning of the author contributions: "These authors contributed equally: C.W., P.F.Z., C.S., and A.J.R.H." The errors have been corrected in the print, PDF and HTML versions of the article.

7.
Nat Med ; 25(3): 496-506, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692699

RESUMO

Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aß plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aß plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aß-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Apolipoproteínas E/imunologia , Doenças das Artérias Carótidas/imunologia , Plexo Corióideo/imunologia , Disfunção Cognitiva/imunologia , Complemento C1q/imunologia , Via Clássica do Complemento/imunologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/imunologia , Animais , Aorta/imunologia , Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/patologia , Encéfalo/imunologia , Encéfalo/patologia , Artérias Carótidas/imunologia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/patologia , Plexo Corióideo/patologia , Disfunção Cognitiva/patologia , Complemento C5 , Feminino , Humanos , Leucócitos , Masculino , Camundongos Knockout para ApoE , Microscopia de Fluorescência , Pessoa de Meia-Idade , Placa Amiloide/imunologia , Placa Amiloide/patologia , Isoformas de Proteínas/imunologia , RNA Interferente Pequeno
8.
Front Immunol ; 10: 2938, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921189

RESUMO

Tertiary lymphoid organs (TLOs) frequently develop locally in adults in response to non-resolving inflammation. Chronic inflammation leads to the differentiation of stromal fibroblast cells toward lymphoid tissue organizer-like cells, which interact with lymphotoxin α 1 ß 2 + immune cells. The interaction initiates lymphoid neogenesis by recruiting immune cells to the site of inflammation and ultimately leads to the formation of TLOs. Mature TLOs harbor a segregated T-cell zone, B-cell follicles with an activated germinal center, follicular dendritic cells, and high endothelial venules, which architecturally resemble those in secondary lymphoid organs. Since CXCL13 and LTα1ß2 play key roles in TLO neogenesis, they might constitute potential biomarkers of TLO activity. The well-developed TLOs actively regulate local immune responses and influence disease progression, and they are thereby regarded as the powerhouses of local immunity. In this review, we recapitulated the determinants for TLOs development, with great emphasis on the fundamental role of chronic inflammation and tissue-resident stromal cells for TLO neogenesis, hence offering guidance for therapeutic interventions in TLO-associated diseases.

9.
Quant Imaging Med Surg ; 8(7): 637-647, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30211031

RESUMO

Background: To quantify the geometrical changes of each neck nodal level (NNL) and estimate the geometric planning target volume (PTV) margin during image-guided radiotherapy (IGRT) for nasopharyngeal cancer (NPC). Methods: Twenty patients with locally advanced NPC underwent one planning computed tomography (CTplan) and 6 weekly repeat CT (CTrep) scans during chemoradiotherapy. Each CTrep was rigidly registered to the CTplan. All the NNLs were manually delineated in each transverse CT section. When comparing the NNL in CTrep with CTplan, their volumes, displacement of the center of the mass, and the shortest perpendicular distance (SPD) were automatically calculated. This was followed by calculation of the systematic and random errors, overlapping index (OI), and dice similarity coefficient (DSC). With PTVs isotropically expanded from NNL by 1, 2, 3, 4, and 5 mm, they were compared with NNL itself; OI >0.95 was defined as the acceptable geometrical coverage. The Mann-Whitney test was used for statistical analysis. Results: All volumes, OI, and DSC of the NNLs (not including level IA) showed a linear decrease over time throughout the treatment course. The volume of NNLs decreased by 1-6% in the first week and 10-21% in the sixth week. The mean SPD was 1.3-1.7 and 1.9-3.5 mm in the first and sixth week respectively. The DSCs for nodal level IB, II, III, and IV were >0.7 and that of level V was <0.7 throughout the treatment course. For level IA and VI, DSC was <0.7 after the 2nd week. To maintain the OI >0.95, 2-5 mm was needed to expand the different NNLs. Conclusions: The geometrical changes of each NNL are substantial and the necessary margin of 2-5 mm depended on individual NNL is needed to maintain geometrical coverage throughout the course of IGRT for NPC.

10.
J Cancer Res Ther ; 14(4): 799-806, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29970656

RESUMO

Aims: We have previously demonstrated that brain metastases were more common among patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) remains inconclusive. In this study, we explored the potential association between EGFR mutation and the risk of ECM. Patients and Methods: Between March 2007 and December 2014, 234 patients were analyzed for the potential association between EGFR mutation and ECM. Statistical Analysis Used: Multivariate Cox regression analysis. Results: There were no associations between the EGFR mutation and metastases in different organs, except for bone. The frequency of EGFR mutation was statistically higher for patients with bone metastases (BMs) at the initial diagnosis (P = 0.039) and at the last follow-up (P = 0.018) as compared to those with wild-type EGFR. In multivariate logistic regression analysis, EGFR mutation significantly increased the risk of BM at the initial diagnosis (P = 0.036). Among those patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly higher in patients with EGFR-mutant disease (P = 0.026). EGFR mutation was an independent risk factor for subsequent BM (P < 0.05). In addition, patients with finial BM and EGFR-mutant disease had longer median survival as compared to those with wild-type disease (P = 0.020). Conclusions: Only BM in patients with ECM was significantly correlated with EGFR mutation during their disease course. EGFR mutation was an independent predictive and prognostic factor for developing BM, which was also a positive predictive factor for overall survival of patients who developed BM.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma de Pulmão , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco
11.
Immunity ; 47(6): 1067-1082.e12, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29246441

RESUMO

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.


Assuntos
Colite/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Repressoras/imunologia , Serina-Treonina Quinases TOR/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular , Colite/genética , Colite/patologia , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/imunologia , Regulação da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/patologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/imunologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Transdução de Sinais , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Serina-Treonina Quinases TOR/genética , Células Th17/imunologia , Células Th17/patologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética
12.
Oncotarget ; 8(31): 51210-51223, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881642

RESUMO

The expression of Programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) has been reported to be reliable prognostic factors in various malignances including primary nasopharyngeal carcinoma (NPC). However, the exact role of PD-1/PD-L1 in recurrent NPC remains unclear. In this study, we aimed to investigate the relationship between the expression of PD-1 / PD-L1 and the clinical-pathology as well the outcomes of recurrent NPC patients (n = 132). The expression of PD-1 and PD-L1 was measured by immunohistochemistry staining. The relationship between PD-1 / PD-L1 and factors involved in clinic-pathology and outcomes of patients with NPC was assessed by correlation analysis. To further explore the association between PD-L1 and anemia, immunofluorescence analysis was performed to investigate the correlation of PD-L1 with hypoxia inducible factor-1α (HIF-1α). We observed that advanced rT classification and anemia status before salvage treatment was associated with high level of PD-L1 in recurrent NPC patients, and PD-L1 and was co-located with HIF-1α in recurrent tumors by immunofluorescence analysis. Moreover, our result suggested that PD-L1 might be a negative indicator for recurrent NPC patients as well as age, rT classification, anemia and tumor necrosis at diagnose of recurrence. Taken together, our results revealed that PD-L1 might be a potential prognostic biomarker for recurrent NPC patients, and advanced re-stage, anemia might represent as candidate biomarkers for evaluating patients' response to anti-PD-1 / PD-L1-treatment. However, further studies are needed to clarify the underlying mechanism of hypoxia in immunosuppression process induced by PD-1 / PD-L1 axis.

13.
Mol Med Rep ; 16(5): 5979-5985, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28849048

RESUMO

The association between inflammatory bowel disease (IBD) and gut microbes has been widely investigated. Our previous study demonstrated that Lactobacillus plantarum LP­Onlly (LP) applied as a probiotic altered the gut flora and attenuated colitis in interleukin (IL)­10 knockout (IL­10­/­) mice. In the present study, metagenome sequencing was performed to investigate the gut microbiome in IL­10­/­mice and the influence of oral administration of LP on microbial composition. Metagenomics sequencing was performed to investigate the influence of IBD on the gut microbiome with and without LP treatment. The alteration of the abundances of various taxonomic and functional groups were investigated across these gut microbiomes. The present study demonstrates that Akkermansia muciniphila was significantly enriched in IL­10­/­ mice, and bacteroides were significantly increased following LP administration. In addition, the phylum Bacteroidetes and Firmicutes were significantly influenced by LP administration. Further characterization of functional capacity revealed that in the gut metagenomes of IL­10­/­mice, genes encoding cell cycle control, replication, recombination, repair and cell envelope biogenesis were decreased, but intracellular trafficking, secretion, and vesicular transport were increased. The present findings indicate that the gut metagenome is associated with IBD, and oral administration of LP contributes to prevention of gut inflammation, providing insight into the treatment of IBD.


Assuntos
Colite/terapia , DNA Bacteriano/genética , Microbioma Gastrointestinal/genética , Interleucina-10/deficiência , Lactobacillus plantarum/fisiologia , Probióticos/farmacologia , Actinobacteria/classificação , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Animais , Bacteroidetes/classificação , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Colite/imunologia , Colite/microbiologia , Colite/patologia , Modelos Animais de Doenças , Feminino , Firmicutes/classificação , Firmicutes/genética , Firmicutes/isolamento & purificação , Deleção de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Interleucina-10/genética , Camundongos , Camundongos Knockout , Proteobactérias/classificação , Proteobactérias/genética , Proteobactérias/isolamento & purificação
14.
Nat Commun ; 8: 15781, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28589929

RESUMO

Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr-/- mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5-/- or Il13-/- ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.


Assuntos
Aterosclerose/patologia , Linfócitos/patologia , Tecido Adiposo Branco/patologia , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Transplante de Medula Óssea , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Linfócitos/metabolismo , Camundongos Knockout para ApoE , Camundongos Mutantes , Placa Aterosclerótica/patologia
15.
J Biol Chem ; 292(22): 9022-9033, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28442573

RESUMO

Histone modifications, including lysine methylation, are epigenetic marks that influence many biological pathways. Accordingly, many methyltransferases have critical roles in various biological processes, and their dysregulation is often associated with cancer. However, the biological functions and regulation of many methyltransferases are unclear. Here, we report that a human homolog of the methyltransferase SET (SU(var), enhancer of zeste, and trithorax) domain containing 3 (SETD3) is cell cycle-regulated; SETD3 protein levels peaked in S phase and were lowest in M phase. We found that the ß-isoform of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7ß) specifically mediates SETD3 degradation. Aligning the SETD3 sequence with those of well known FBXW7 substrates, we identified six potential non-canonical Cdc4 phosphodegrons (CPDs), and one of them, CPD1, is primarily phosphorylated by the kinase glycogen synthase kinase 3 (GSK3ß), which is required for FBXW7ß-mediated recognition and degradation. Moreover, depletion or inhibition of GSK3ß or FBXW7ß resulted in elevated SETD3 levels. Mutations of the phosphorylated residues in CPD1 of SETD3 abolished the interaction between FBXW7ß and SETD3 and prevented SETD3 degradation. Our data further indicated that SETD3 levels positively correlated with cell proliferation of liver cancer cells and liver tumorigenesis in a xenograft mouse model, and that overexpression of FBXW7ß counteracts the SETD3's tumorigenic role. We also show that SETD3 levels correlate with cancer malignancy, indicated by SETD3 levels that the 54 liver tumors are 2-fold higher than those in the relevant adjacent tissues. Collectively, these data elucidated that a GSK3ß-FBXW7ß-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates its oncogenic role in liver tumorigenesis.


Assuntos
Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteólise , Substituição de Aminoácidos , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Proteína 7 com Repetições F-Box-WD , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HeLa , Xenoenxertos , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Nus , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
16.
Sci Rep ; 7: 43627, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28256540

RESUMO

Programmed death-1 (PD-1) is an immunosuppressive receptor functionally bound with programmed death-ligand 1 (PD-L1), which has been reported in various malignancies. However, only a few studies are available for the clinical significance of PD-1/PD-L1 in nasopharyngeal carcinoma (NPC). In this study, we aim to investigate alterations in PD-1/PD-L1 by using immunohistochemistry analysis in a cohort of consecutively enrolled NPC patients (n = 99). To further analyse the correlation between PD-1/PD-L1 and factors involved in clinico-pathology, haematologic biomarkers, EBV-DNA load and outcomes, we collected clinical data for statistical analysis. We observed that lower haemoglobin (HB) and Body Mass Index (BMI) levels were associated with high levels of PD-L1 staining in NPC patients. Importantly, our results suggested that PD-L1 might be a negative indicator for NPC patients. In contrast, a correlation between the PD-1/PD-L1 level and EBV load was not identified. Moreover, PD-1 positivity was suggested to not be significantly correlated with clinical outcomes. Taken together, our results revealed that PD-L1 might be a potential prognostic biomarker for NPC patients. However, further studies are needed to clarify the underlying mechanism of EBV status in the immunosuppression process induced by the PD-1/PD-L1 axis.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma/metabolismo , Carcinoma/mortalidade , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidade , Adulto , Idoso , Biópsia , Carcinoma/diagnóstico , Carcinoma/etiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Expressão Gênica , Herpesvirus Humano 4/genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/etiologia , Estadiamento de Neoplasias , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Carga Viral , Adulto Jovem
17.
Oncotarget ; 7(35): 56998-57010, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27486770

RESUMO

Lung adenocarcinomas are more commonly associated with brain metastases (BM). Epidermal growth factor receptor (EGFR) mutations have been demonstrated to be both predictive and prognostic for patients with lung adenocarcinoma. We aimed to explore the potential association between EGFR mutation and the risk of BM in pulmonary adenocarcinoma patients. Data of 234 patients from 2007 to 2014 were retrospectively reviewed. A total of 108 patients had EGFR mutations in the entire cohort. Among them, 76 patients developed BM during their disease course. The incidence of BM was statistically higher in patients with EGFR mutations both at initial diagnosis (P=0.014) and at last follow-up (P<0.001). Multivariate logistic regression analysis revealed that EGFR mutation significantly increased the risk of BM at initial diagnosis (OR=2.515, P=0.022). In patients without BM at initial diagnosis, the accumulative rate of subsequent BM was significantly higher with EGFR mutations (P=0.001). Multivariate Cox regression analysis identified EGFR mutation as the only independent risk factor for subsequent BM (HR=3.036, P=0.001). Patients with EGFR mutations demonstrated longer overall survival (OS) after BM diagnosis than patients with wild-type EGFR (P=0.028). Our data suggest that EGFR mutation is an independent predictive and prognostic risk factor for BM and a positive predictive factor for OS in patients with BM.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Encefálicas/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/metabolismo , Mutação , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Análise Mutacional de DNA , Receptores ErbB/metabolismo , Éxons , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
18.
Bio Protoc ; 6(11)2016 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-27366759

RESUMO

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. Apolipoprotein E-deficient (ApoE-/-) mice are used as experimental models to study human atherosclerosis. ApoE-/- mice are constitutively hyperlipidemic and develop intima plaques that resemble human plaques. Various issues including experimental design for lesion analysis, dietary conditions, isolation of the aorta, staining methods, morphometry, group size, age, the location within the arterial tree, and statistical analyses are important parameters that need to be addressed to obtain robust data. Here, we provide detailed methods to quantify aorta atherosclerosis.

19.
Bio Protoc ; 6(11)2016 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-27335895

RESUMO

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by lipid deposition, plaque formation, and immune cell infiltration. Innate and adaptive immune cells infiltrate the artery during development of the disease. Moreover, advanced disease leads to formation of artery tertiary lymphoid organs in the adventitia (Grabner et al., 2009; Hu et al., 2015). Various and diverse types of immune cells have been identified in the aorta adventitia vs atherosclerotic plaques (Elewa et al., 2016; Galkina et al., 2006; Lotzer et al., 2010; Mohanta et al., 2016; Mohanta et al., 2014; Moos et al., 2005; Srikakulapu et al., 2016; Zhao et al., 2004). There are conflicting reports on the number and subtypes of immune cells in the aorta depending on the age of the animals, the protocol that is used to obtain single cell suspensions, and the dietary conditions of the mice (Campbell et al., 2012; Clement et al., 2015; Galkina et al., 2006; Kyaw et al., 2012). The number of immune cells in the aorta differs as much as tenfold using different protocols (Butcher et al., 2012; Galkina et al., 2006; Gjurich et al., 2015; Grabner et al., 2009; Hu et al., 2015). These discrepant results call for a protocol that robustly documents bona fide aorta cells rather than those in the surrounding tissues or blood. Critical methodological hurdles include the removal of adjacent adipose tissue and small paraaortic lymph nodes lining the entire aortic tree that are not visible by the naked eye. A dissection microscope is therefore recommended. Moreover protocols of aorta preparations should ascertain that lymphocyte aggregates referred to as fat associated lymphoid clusters (FALCs) (Benezech et al., 2015; Elewa et al., 2015) that are often present at the border between the adipose tissue and the adventitia are removed before enzyme digestion. We propose - besides other approaches (Hu et al., 2015; Mohanta et al., 2014) - a combination of immunohistochemical staining and fluorescence activated cell sorter (FACS) analyses from single cell suspensions to quantify the cells of interest. This protocol describes isolation of single cells from mouse aorta for FACS and other analysis.

20.
Biochem Biophys Res Commun ; 477(2): 174-80, 2016 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-27291151

RESUMO

Dysregulation of mammalian target of rapamycin (mTOR) signaling contributes to head and neck squamous cell carcinoma (HNSCC) tumorigenesis and progression. In the current study, we tested the anti-HNSCC cell activity by GDC-0349, a selective ATP-competitive inhibitor of mTOR. We showed that GDC-0349 inhibited proliferation of established and primary human HNSCC cells bearing high-level of p-AKT/p-S6K. Further, it induced caspase-dependent apoptosis in the HNSCC cells. GDC-0349 blocked mTORC1 and mTORC2 activation, yet it simultaneously induced autophagy activation in HNSCC cells. The latter was evidenced by induction of LC3B-II, Beclin-1 and Autophagy-related (ATG)-7, as well as downregulation of p62. Autophagy inhibitors (3-methyladenine and bafilomycin A1) or ATG-7 siRNA dramatically potentiated GDC-0349's cytotoxicity against HNSCC cells. Intriguingly, we showed that ceramide (C14), a pro-apoptotic sphingolipid, also induced ATG-7 degradation, and sensitized HNSCC cells to GDC-0349. Collectively, the preclinical study provided evidences to support GDC-0349 as a promising anti-HNSCC agent. GDC-0349 sensitization may be achieved via autophagy inhibition.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento
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