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1.
EMBO Mol Med ; : e14563, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34585848

RESUMO

Semaphorin 7A (SEMA7A) is a membrane-bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC-MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance-associated protein-2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

2.
Aging (Albany NY) ; 13(17): 21483-21496, 2021 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511433

RESUMO

2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.

3.
Eur J Gastroenterol Hepatol ; 32(9): 1116-1122, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649329

RESUMO

BACKGROUND: Although the efficacy of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) for primary biliary cholangitis (PBC) has been suggested by small trials, a meta-analysis to summarize the evidence has not yet been carried out. The aim of this study was to evaluate the clinical outcomes of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC. METHODS AND MATERIALS: We searched the PubMed, EMBASE, the web of science, and the Cochrane Library databases for English-language studies published before September 2018. Studies were included if they were randomized controlled trials (RCTs) and reported relative risk (RR) estimates with 95% confidence intervals (CIs) or related data for the clinical outcomes of different therapies in patients with PBC. RESULTS: Of the 1169 titles identified, two studies meeting the inclusion criteria were included in the meta-analysis. Approximately 222 patients with PBC were included in this analysis. The results of this study indicated that combination therapy was significantly superior to monotherapy in reducing serum alanine transaminase (mean difference: -15.63 IU/L; 95% CI, -21.59 to -9.68), aspartate transaminase (mean difference: -6.63 IU/L; 95% CI, -11.03 to -2.24), gamma-glutamyl transpeptidase (mean difference: -131.30 IU/L; 95% CI, -177.52 to -85.08), and C-reactive protein (mean difference = -1.17 mg/L; 95% CI, -2.19 to -0.14), but NS in improving primary endpoints of alkaline phosphatase level with 15.0% reduction from baseline, and equal or higher than the upper limit of normal serum total bilirubin (RR = 2.75; 95% CI, 0.43-17.68), conjugated bilirubin (mean difference = -0.06 mg/dL; 95% CI, -0.28 to 0.15), IgM (mean difference = -41.18 mg/dL; 95% CI, -244.45 to 162.09), and adverse events (P > 0.05). CONCLUSION: This meta-analysis demonstrated that combination therapy with UDCA and OCA provided satisfactory clinical outcomes, which may be a promising alternative for patients with PBC who had an inadequate response to UDCA therapy. Therefore, high-quality RCTs on the safety and efficacy of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC should be performed in the future.

5.
Mol Cancer Ther ; 16(10): 2094-2106, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698199

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. In vitro radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that A20 was a direct target of miR-125b and found that miR-125b regulated NPC cell radioresponse by targeting A20/NF-κB signaling. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 overexpression decreased while A20 knockdown increased NPC cell radioresistance both in vitro and in vivo Moreover, A20 was significantly downregulated while p-p65 (RelA) significantly upregulated in the radioresistant NPCs relative to radiosensitive NPCs, and miR-125b expression level was negatively associated with A20 expression level, whereas positively associated with p-p65 (RelA) level. Our data demonstrate that miR-125b and A20 are critical regulators of NPC radioresponse, and high miR-125b expression enhances NPC radioresistance through targeting A20 and then activating the NF-κB signaling pathway, highlighting the therapeutic potential of the miR-125b/A20/NF-κB axis in clinical NPC radiosensitization. Mol Cancer Ther; 16(10); 2094-106. ©2017 AACR.


Assuntos
Carcinoma/radioterapia , MicroRNAs/genética , Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação/genética , Fator de Transcrição RelA/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Animais , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , NF-kappa B/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cell Death Dis ; 8(6): e2855, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569771

RESUMO

MiR-125b is aberrantly expressed and has a role in the various types of tumors. However, the role and mechanism of miR-125b in nasopharyngeal carcinoma (NPC) are unclear. In this study, we investigated the role and mechanism of miR-125b in NPC. We observed that miR-125b was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM), and its increment was correlated with poor patient survival, and was an independent predictor for reduced patient survival; miR-125b promoted NPC cell proliferation and inhibited NPC cell apoptosis; in a mouse model, administration of miR-125b antagomir significantly reduced the growth of NPC xenograft tumors. Mechanistically, we confirmed that A20 was a direct target of miR-125b, and found that activation of nuclear factor κB (NF-κB) signaling pathway by A20 mediated miR-125b-promoting NPC cell proliferation and -inhibiting NPC cell apoptosis. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors. Moreover, A20 was significantly downregulated, whereas p-p65(RelA) was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa, and miR-125b level was negatively associated with A20 level, whereas positively associated with p-p65 level. Our data demonstrate that miR-125b regulates NPC cell proliferation and apoptosis by targeting A20/NF-κB signaling pathway, and miR-125b acts as oncogene, whereas A20 functions as tumor suppressor in NPC, highlighting the therapeutic potential of miR-125b/A20/NF-κB signaling axis in the NPC.


Assuntos
Apoptose/genética , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição RelA/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Transplante de Neoplasias , Transdução de Sinais , Análise de Sobrevida , Fator de Transcrição RelA/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
7.
Oncotarget ; 7(10): 11463-77, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26862850

RESUMO

Raf kinase inhibitory protein (RKIP) functions as a chemo-immunotherapeutic sensitizer of cancers, but regulation of RKIP on tumor radiosensitivity remains largely unexplored. In this study, we investigate the role and mechanism of RKIP in nasopharyngeal carcinoma (NPC) radioresistance. The results showed that RKIP was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its reduction correlated with NPC radioresistance and poor patient survival, and was an independent prognostic factor. In vitro radioresponse assay showed that RKIP overexpression decreased while RKIP knockdown increased NPC cell radioresistance. In the NPC xenografts, RKIP overexpression decreased while RKIP knockdown increased tumor radioresistance. Mechanistically, RKIP reduction promoted NPC cell radioresistance by increasing ERK and AKT activity, and AKT may be a downstream transducer of ERK signaling. Moreover, the levels of phospho-ERK-1/2 and phospho-AKT were increased in the radioresistant NPC tissues compared with radiosensitive ones, and negatively associated with RKIP expression, indicating that RKIP-regulated NPC radioresponse is mediated by ERK and AKT signaling in the clinical samples. Our data demonstrate that RKIP is a critical determinant of NPC radioresponse, and its reduction enhances NPC radioresistance through increasing ERK and AKT signaling activity, highlighting the therapeutic potential of RKIP-ERK-AKT signaling axis in NPC radiosensitization.


Assuntos
Carcinoma/enzimologia , Carcinoma/radioterapia , Sistema de Sinalização das MAP Quinases/genética , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/radioterapia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Animais , Carcinoma/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Proteína Oncogênica v-akt , Tolerância a Radiação , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Oncol Rep ; 34(5): 2585-601, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26330189

RESUMO

Nasopharyngeal carcinoma (NPC) is commonly diagnosed in southern Asia. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. Increasing evidence suggests that the dysregulation of miRNAs promotes NPC tumorigenesis. Epstein-Barr virus (EBV) infection and EBV-encoded miRNAs are also associated with the development of NPC. However, it is unclear how cellular and EBV miRNAs jointly regulate target genes and signaling pathways in NPC. In the present study, we analyzed the differential cellular and EBV miRNA expression profiles in 20 pooled NPC tissues using microarrays. We found that 19 cellular miRNAs and 9 EBV miRNAs were upregulated and 31 cellular miRNAs were downregulated in NPC tissues. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the 19 upregulated miRNAs target mainly the p53 signaling pathway in cancer, whereas the downregulated miRNAs regulate pathways related to cancer, focal adhesion and Erb, and MAPK signaling. In contrast, the upregulated EBV miRNAs target primarily the TGF-ß and Wnt signaling pathways. Data also suggested that cellular miR-34b, miR-34c, miR-18a, miR­200a/b, miR-449a, miR-31 and let-7 may be dysregulated in NPCs, and that the aberrant activation of their target genes in the p53 pathway and cell cycle enhance NPC cell survival and proliferation. In addition, EBV-miRNAs such as BART3 and BART5 target genes in the p53, TGF-ß and Wnt signaling pathways to modulate NPC apoptosis and transformation. To better elucidate the interaction between miRNAs and target genes, we constructed an anti-correlated cellular and EBV miRNA/target gene regulatory network. The current findings may help dissect the roles played by cellular and EBV miRNAs during NPC tumorigenesis, and also provide useful biomarkers for the diagnosis and treatment of NPCs.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Perfilação da Expressão Gênica/métodos , Herpesvirus Humano 4/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/virologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Carcinoma , Ciclo Celular , Proliferação de Células , Infecções por Vírus Epstein-Barr/patologia , Adesões Focais/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , RNA Viral/genética , Fator de Crescimento Transformador beta/genética , Proteína Supressora de Tumor p53/genética , Via de Sinalização Wnt
9.
Mol Cancer Ther ; 14(11): 2653-64, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26304234

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA (miR) regulates this phenomenon. In this study, we investigated the function and mechanism of miR-203 in NPC radioresistance, one of downregulated miRs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-203 was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its decrement significantly correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that miR-203 mimic markedly decreased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-203 agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that IL8 was a direct target of miR-203, and found that reduced miR-203 promoted NPC cell radioresistance by activating IL8/AKT signaling. Moreover, the levels of IL8 and phospho-AKT were significantly increased in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and negatively associated with miR-203 level. Our data demonstrate that miR-203 is a critical determinant of NPC radioresponse, and its decrement enhances NPC radioresistance through targeting IL8/AKT signaling, highlighting the therapeutic potential of the miR-203/IL8/AKT signaling axis in NPC radiosensitization.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Interleucina-8/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Western Blotting , Carcinoma , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imuno-Histoquímica , Interleucina-8/metabolismo , Masculino , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/radioterapia , Fosforilação/efeitos da radiação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tolerância a Radiação/genética , Radioterapia/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos da radiação , Análise de Sobrevida , Carga Tumoral/genética , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncotarget ; 6(29): 28341-56, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26314966

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-23a in NPC radioresistance, one of downregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-23a was frequently downregulated in the radioresistant NPC tissues, and its decrement correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that restoration of miR-23a expression markedly increased NPC cell radiosensitivity. In a mouse model, therapeutic administration of miR-23a agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we found that reduced miR-23a promoted NPC cell radioresistance by activating IL-8/Stat3 signaling. Moreover, the levels of IL-8 and phospho-Stat3 were increased in the radioresistance NPC tissues, and negatively associated with miR-23a level. Our data demonstrate that miR-23a is a critical determinant of NPC radioresponse and prognostic predictor for NPC patients, and its decrement enhances NPC radioresistance through activating IL-8/Stat3 signaling, highlighting the therapeutic potential of miR-23a/IL-8/Stat3 signaling axis in NPC radiosensitization.


Assuntos
Interleucina-8/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Western Blotting , Carcinoma , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Interleucina-8/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/radioterapia , Prognóstico , Interferência de RNA , Tolerância a Radiação/genética , Radiação Ionizante , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 6(18): 16422-36, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-25915430

RESUMO

The role and underlying mechanism of Raf kinase inhibitory protein (RKIP) in nasopharyngeal carcinoma (NPC) metastasis remain unclear. Here, we showed that RKIP was downregulated in the NPC with high metastatic potentials, and its decrement correlated with NPC metastasis and poor patient survival, and was an independent predictor for reduced overall survival. With a combination of loss-of-function and gain-of-function approaches, we observed that high expression of RKIP reduced invasion, metastasis and epithelial to mesenchymal transition (EMT) marker alternations of NPC cells. We further showed that RKIP overexpression attenuated while RKIP knockdown enhanced Stat3 phosphorylation and activation in NPC cells; RKIP reduced Stat3 phosphorylation through interacting with Stat3; Stattic attenuated NPC cell migration, invasion and EMT marker alternations induced by RKIP knockdown, whereas Stat3 overexpression restored NPC cell migration, invasion and EMT marker alternations reduced by RKIP overexpression. In addition, there was an inverse correlation between RKIP and phospho-Stat3 expression in the NPC tissues and xenograft metastases. Our data demonstrate that RKIP is a metastatic suppressor and predictor for metastasis and prognosis in NPC, and RKIP downregulation promotes NPC invasion, metastasis and EMT by activating Stat3 signaling, suggesting that RKIP/Stat3 signaling could be used as a therapeutic target for NPC metastasis.


Assuntos
Neoplasias Pulmonares/secundário , Metástase Linfática/patologia , Neoplasias Nasofaríngeas/patologia , Proteína de Ligação a Fosfatidiletanolamina/biossíntese , Fator de Transcrição STAT3/metabolismo , Animais , Carcinoma , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo , Ativação Enzimática/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Invasividade Neoplásica/genética , Transplante de Neoplasias , Proteína de Ligação a Fosfatidiletanolamina/genética , Fosforilação/genética , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais/genética
12.
PLoS One ; 9(1): e87767, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24498188

RESUMO

BACKGROUND: The purpose of this study was to identify miRNAs and genes involved in nasopharyngeal carcinoma (NPC) radioresistance, and explore the underlying mechanisms in the development of radioresistance. METHODS: We used microarrays to compare the differences of both miRNA and mRNA expression profiles in the radioresistant NPC CNE2-IR and radiosensitive NPC CNE2 cells, applied qRT-PCR to confirm the reliability of microarray data, adopted databases prediction and anticorrelated analysis of miRNA and mRNA expression to identify the miRNA target genes, and employed bioinformatics tools to examine the functions and pathways in which miRNA target genes are involved, and construct a miRNA-target gene regulatory network. We further investigated the roles of miRNA-23a and its target gene IL-8 in the NPC radioresistance. RESULTS: THE MAIN FINDINGS WERE FOURFOLD: (1) fifteen differential miRNAs and 372 differential mRNAs were identified, and the reliability of microarray data was validated for randomly selected eight miRNAs and nine genes; (2) 174 miRNA target were identified, and most of their functions and regulating pathways were related to tumor therapeutic resistance; (3) a posttranscriptional regulatory network including 375 miRNA-target gene pairs was constructed, in which the ten genes were coregulated by the six miRNAs; (4) IL-8 was a direct target of miRNA-23a, the expression levels of IL-8 were elevated in the radioresistant NPC tissues and showed inverse correlation with miRNA-23a expression, and genetic upregulation of miRNA-23a and antibody neutralization of secretory IL-8 could reduce NPC cells radioresistance. CONCLUSIONS: We identified fifteen differential miRNAs and 372 differential mRNAs in the radioresistant NPC cells, constructed a posttranscriptional regulatory network including 375 miRNA-target gene pairs, discovered the ten target genes coregulated by the six miRNAs, and validated that downregulated miRNA-23a was involved in NPC radioresistance through directly targeting IL-8. Our data form a basis for further investigating the mechanisms of NPC radioresistance.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Neoplasias Nasofaríngeas/metabolismo , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Tolerância a Radiação , Carcinoma , Linhagem Celular Tumoral , Humanos , MicroRNAs/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , RNA Mensageiro/genética , RNA Neoplásico/genética
13.
PLoS One ; 8(8): e71865, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23977169

RESUMO

BACKGROUND: Our quantitative proteomic study showed that selenium-binding protein 1 (SELENBP1) was progressively decreased in human bronchial epithelial carcinogenic process. However, there is little information on expression and function of SELENBP1 during human lung squamous cell cancer (LSCC) carcinogenesis. METHODS: iTRAQ-tagging combined with 2D LC-MS/MS analysis was used to identify differentially expressed proteins in the human bronchial epithelial carcinogenic process. SELENBP1, member of selenoproteins family and progressively downregulated in this process, was selected to further study. Both Western blotting and immunohistochemistry were performed to detect SELENBP1 expression in independent sets of tissues of bronchial epithelial carcinogenesis, and ability of SELENBP1 for discriminating NBE (normal bronchial epithelium) from preneoplastic lesions from invasive LSCC was evaluated. The effects of SELENBP1 downregulation on the susceptibility of benzo(a)pyrene (B[a]P)-induced human bronchial epithelial cell transformation were determined. RESULTS: 102 differentially expressed proteins were identified by quantitative proteomics, and SELENBP1 was found and confirmed being progressively decreased in the human bronchial epithelial carcinogenic process. The sensitivity and specificity of SELENBP1 were 80% and 79% in discriminating NBE from preneoplastic lesions, 79% and 82% in discriminating NBE from invasive LSCC, and 77% and 71% in discriminating preneoplastic lesions from invasive LSCC, respectively. Furthermore, knockdown of SELENBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly increased the efficiency of B[a]P-induced cell transformation. CONCLUSIONS: The present data shows for the first time that decreased SELENBP1 is an early event in LSCC, increases B[a]P-induced human bronchial epithelial cell transformation, and might serve as a novel potential biomarker for early detection of LSCC.


Assuntos
Brônquios/patologia , Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Ligação a Selênio/genética , Sequência de Aminoácidos , Apoptose , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Ciclo Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Microdissecção e Captura a Laser , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Dados de Sequência Molecular , Proteoma/genética , Proteoma/metabolismo , Curva ROC , Mucosa Respiratória/patologia , Proteínas de Ligação a Selênio/química , Proteínas de Ligação a Selênio/metabolismo , Espectrometria de Massas em Tandem
14.
Oncol Rep ; 30(1): 341-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23677397

RESUMO

To discover novel lung adenocarcinoma (AdC) biomarkers, isobaric tags for relative and absolute quantitation (iTRAQ)-tagging combined with 2D-LC-MS/MS analysis was used to identify differentially expressed plasma membrane proteins in lung AdC and paired paraneoplastic normal lung tissues (PNLTs) adjacent to tumors. In this study, significant caveolin-1 downregulation and integrin ß1 upregulation was observed in primary lung AdC vs. PNLT. As there has been no report on the association of integrin ß1 with lung AdC, immunohistochemical staining was performed to detect the expression of integrin ß1 in an independent set of archival tissue specimens including 42 cases of PLNT, 46 cases of without lymph node metastasis primary AdC (non-LNM AdC) and 62 cases of LNM AdC; the correlation of their expression levels with clinicopathological characteristics and clinical outcomes were evaluated. Based on the data, upregulation of integrin ß1 was significantly correlated with advanced clinical stage and lymph node metastasis. Integrin ß1 overexpression was significantly associated with advanced clinical stage (P<0.05), lymph node metastasis (P<0.05), increased relapse rate (P<0.05) and decreased overall survival (P<0.05) in AdCs. Cox regression analysis indicated that integrin ß1 overexpression is an independent prognostic factor. The data suggest that integrin ß1 is a potential biomarker for LNM and prognosis of AdC and integrin ß1 upregulation may play an important role in the pathogenesis of AdC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Integrina beta1/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão , Biomarcadores Tumorais , Cromatografia Líquida , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Prognóstico , Sobrevida , Espectrometria de Massas em Tandem , Regulação para Cima
15.
Med Hypotheses ; 81(1): 68-70, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23660133

RESUMO

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), but radioresistance remains a serious obstacle to successful treatment in many cases. Therefore, the biomarkers for predicting NPC response to radiotherapy are very important for targeted therapy and individualized radiotherapy of NPC. Accumulating evidences have shown that Annexin A1 was correlated with NPC radioresistance. First, Annexin A1 is a potential tumor suppressor gene, and can regulate tumor cell proliferation and apoptosis, thus abnormal expression of Annexin A1 in NPC affects apoptosis of tumor cells induced by ionizing radiation and radiotherapeutic efficacy. Second, Annexin A1 is one of the proteins that are involved in p53-mediated radioresponse in NPC, and it might be related to NPC radioresistance. Third, the expression level of Annexin A1 is down-regulated in NPC, and is correlated with metastasis, recurrence and poor prognosis of NPC, thus Annexin A1 downregulation may increase NPC radioresistance, leading to poor prognosis. Last but not the least, Annexin A1 is closely related with tumor chemoresistance, whereas radioresistance is similar to chemoresistance in many aspects, thus Annexin A1 may also be involved in NPC radioresistance. Based on the above mentions, we hypothesize that Annexin A1 is closely correlated with NPC radioresistance and is an important new biomarker for predicting NPC response to radiotherapy.


Assuntos
Anexina A1/análise , Biomarcadores Tumorais/análise , Neoplasias Nasofaríngeas/radioterapia , Radioterapia/normas , Humanos , Neoplasias Nasofaríngeas/metabolismo
16.
J Proteomics ; 77: 202-14, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22982323

RESUMO

To identify a novel lung adenocarcinoma (AdC) biomarker, iTRAQ-tagging combined with 2D LC-MS/MS analysis was used to identify differentially expressed plasma membrane (PM) proteins in primary lung AdCs and paraneoplastic normal lung tissues (PNLTs). As a result, 36 differentially expressed membrane proteins were identified. Two differential PM proteins flotillin-1 and caveolin-1 were selectively validated by Western blotting. As there has been no report on the association of flotillin-1 with lung AdC, immunohistochemistry was further performed to detect the expression of flotillin-1 in the archival tissue specimens including 42 cases of PNLTs, 62 cases of primary lung AdCs with lymph node metastasis (LNM AdCs), and 46 cases of primary lung AdCs without lymph node metastasis (non-LNM AdCs), and the correlation of flotillin-1 expression levels in lung AdCs with clinicopathological features and clinical outcomes were evaluated. The results showed that up-regulation of flotillin-1 expression in lung AdCs was significantly correlated with advanced clinical stage, lymph node metastasis, increased postoperative relapse and decreased overall survival. Cox regression analysis revealed that the expressional level of flotillin-1 was an independent prognostic factor. The data suggest that flotillin-1 is a potential novel biomarker for lymph node metastasis and prognosis of lung AdC, and flotillin-1 up-regulation might play an important role in the pathogenesis of lung AdC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Proteoma/biossíntese , Adenocarcinoma/patologia , Adulto , Membrana Celular/metabolismo , Membrana Celular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Taxa de Sobrevida , Regulação para Cima
17.
J Cancer Res Clin Oncol ; 138(12): 2117-25, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22847231

RESUMO

PURPOSE: To identify the proteins involved in radioresistance in nasopharyngeal cancer (NPC) cells. METHODS: Sublethal ionizing radiation was applied to establish a radioresistant NPC cell line from its parental NPC cell line CNE1. Clonogenic survival assay, cell growth assay and flow cytometry analysis were used to examine the difference of radiosensitivity in the radioresistant CNE1 cells (CNE1-IR) and control CNE1 cells. Comparative proteomics was performed to identify the differential proteins in the two cell lines. Association of HSP27, one of upregulated proteins in CNE1-IR cells, with NPC cell radioresistance was selected for further investigation using antisense oligonucleotides (ASOs), clonogenic survival assay, Hoechst 33258 staining of apoptotic cells and MTT assay of cell viability. RESULTS: Radioresistant NPC cell line CNE1-IR derived from its parental cell line CNE1 was established. Thirteen differential proteins in the CNE1-IR and CNE1 cells were identified by proteomics, and differential expression of HSP27, one of identified proteins, was selectively confirmed by western blot. Inhibition of HSP27 expression by HSP27 ASOs decreased clonogenic survival and cell viability and increased cell apoptosis of CNE1-IR cells after irradiation, that is, enhanced radiosensitivity of CNE1-IR cells. CONCLUSION: The data suggest that HSP27 is a radioresistant protein in NPC cells, and its upregulation may be involved in the NPC radioresistance.


Assuntos
Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Apoptose/genética , Apoptose/efeitos da radiação , Carcinoma , Ciclo Celular/genética , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Regulação para Baixo/efeitos da radiação , Proteínas de Choque Térmico , Humanos , Chaperonas Moleculares , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteômica/métodos , Tolerância a Radiação/genética , Regulação para Cima/efeitos da radiação
18.
Mol Cell Proteomics ; 11(6): M111.013946, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22298307

RESUMO

To discover novel biomarkers for early detection of human lung squamous cell cancer (LSCC) and explore possible mechanisms of LSCC carcinogenesis, iTRAQ-tagging combined with two dimensional liquid chromatography tandem MS analysis was used to identify differentially expressed proteins in human bronchial epithelial carcinogenic process using laser capture microdissection-purified normal bronchial epithelium (NBE), squamous metaplasia (SM), atypical hyperplasia (AH), carcinoma in situ (CIS) and invasive LSCC. As a result, 102 differentially expressed proteins were identified, and three differential proteins (GSTP1, HSPB1 and CKB) showing progressively expressional changes in the carcinogenic process were selectively validated by Western blotting. Immunohistochemistry was performed to detect the expression of the three proteins in an independent set of paraffin-embedded archival specimens including various stage tissues of bronchial epithelial carcinogenesis, and their ability for early detection of LSCC was evaluated by receiver operating characteristic analysis. The results showed that the combination of the three proteins could perfectly discriminate NBE from preneoplastic lesions (SM, AH and CIS) from invasive LSCC, achieving a sensitivity of 96% and a specificity of 92% in discriminating NBE from preneoplatic lesions, a sensitivity of 100% and a specificity of 98% in discriminating NBE from invasive LSCC, and a sensitivity of 92% and a specificity of 91% in discriminating preneoplastic lesions from invasive LSCC, respectively. Furthermore, we knocked down GSTP1 in immortalized human bronchial epithelial cell line 16HBE cells, and then measured their susceptibility to carcinogen benzo(a)pyrene-induced cell transformation. The results showed that GSTP1 knockdown significantly increased the efficiency of benzo(a)pyrene-induced 16HBE cell transformation. The present data first time show that GSTP1, HSPB1 and CKB are novel potential biomarkers for early detection of LSCC, and GSTP1 down-regulation is involved in human bronchial epithelial carcinogenesis.


Assuntos
Biomarcadores Tumorais/metabolismo , Detecção Precoce de Câncer , Neoplasias Pulmonares/metabolismo , Neoplasias de Células Escamosas/metabolismo , Sequência de Aminoácidos , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Brônquios/patologia , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Análise por Conglomerados , Creatina Quinase Forma BB/química , Creatina Quinase Forma BB/genética , Creatina Quinase Forma BB/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Expressão Gênica , Glutationa S-Transferase pi/química , Glutationa S-Transferase pi/genética , Glutationa S-Transferase pi/metabolismo , Proteínas de Choque Térmico HSP27/química , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Microdissecção e Captura a Laser , Neoplasias Pulmonares/diagnóstico , Chaperonas Moleculares , Dados de Sequência Molecular , Neoplasias de Células Escamosas/diagnóstico , Proteômica , Curva ROC , Estatísticas não Paramétricas , Espectrometria de Massas em Tandem
19.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 37(1): 17-26, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22349375

RESUMO

OBJECTIVE: To identify proteins associated with nasopharyngeal carcinoma (NPC) metastasis, and provide scientific basis for the prevention and cure of NPC. METHODS: A two-dimensional gel electrophoresis and mass spectrometry were performed to screen for differential proteins between highly metastatic 5-8F and non-metastatic 6-10B NPC cell lines. Western blot was used to confirm the differential proteins. We siRNA used to inhibit the expression of differential protein nm23-H1 to determine the association of nm23-H1 with NPC in vitro invasive ability. Immunohistochemistry and statistics were used to evaluate the correlation of nm23-H1 expression with clinicopathological features and clinical outcomes in paraffin-embedded archival tissues including 93 cases of primary NPC and 20 cases of cervical lymphonode metastatic NPC (LMNPC). RESULTS: A total of 15 differential proteins in the 2 cell lines were identified by a proteomic approach, and 3 differential proteins were selectively confirmed. Downregulation of nm23-H1 by siRNA significantly increased the in vitro invasive ability of 6-10B. Significant nm23-H1 downregulation was observed in LMNPC compared with primary NPC. nm23-H1 downregulation in primary NPC was positively correlated with lymphonode and distant metastasis, advanced clinical stage and recurrence. Survival curves showed that patients with nm23-H1 downregulation in primary NPC had a poor prognosis. Multivariate analysis confirmed that nm23-H1 expression level in primary NPC was an independent prognostic indicator. CONCLUSION: nm23-H1 behaves as a metastasis suppressor in NPC, and nm23-H1 downregulation in the is a biomarker for poor NPC prognosis.


Assuntos
Nucleosídeo NM23 Difosfato Quinases/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteômica/métodos , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Eletroforese em Gel Bidimensional , Humanos , Espectrometria de Massas , Nucleosídeo NM23 Difosfato Quinases/genética , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Proteínas Supressoras de Tumor/genética
20.
J Cancer Res Clin Oncol ; 137(12): 1831-40, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21922325

RESUMO

PURPOSE: To identify methylation-silenced genes in acute myeloid leukemia (AML). METHODS: Microarray analyses were performed in AML cell line HL-60 cells exposed to the demethylating agent 5-aza-2dC. The methylation status and expression of glioma pathogenesis-related protein 1 (GLIPR1), one of highly induced genes by demethylation, were further detected in six hematopoietic malignancy cell lines and 260 bone marrow samples from leukemia patients and nonmalignant diseases as control, as well as pre-treated and post-treated bone marrow samples from 24 complete remission AML patients received chemotherapy using MS-PCR, bisulfite DNA sequencing, RT-PCR, and Western blotting. RESULTS: One hundred and nine genes were significantly induced by demethylation in HL-60 cells, 12 genes of which were confirmed by RT-PCR. GLIPR1, a tumor suppressor gene, was frequently methylation-silenced in AML cell lines and AML patients, but not in the other hematopoietic malignancy cell lines and patients. The frequencies of methylation-silenced GLIPR1 in the pre-treatment were significantly higher than those in the post-treatment in complete remission AML patients. CONCLUSION: We identify 109 genes induced by demethylation in HL-60 cells, and demonstrate that GLIPR1 is a methylation-silenced gene in the AML patients, and may serve as a marker for monitoring disease activity during therapy in the AML patients. The data provide the important information for studying the pathogenesis of AML and discovering the target genes of methylating agents.


Assuntos
Metilação de DNA , Inativação Gênica , Genes Supressores de Tumor , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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