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To determine the role of miR-25 in non-small cell lung cancer (NSCLC), we first detected miR-25 expression in clinical specimens and lung cancer cell lines by quantitative real-time polymerase chain reaction. The levels of miR-25 were elevated in the plasma of NSCLC patients and NSCLC cell lines. Transfection of A549 and 95-D cells with a miR-25 inhibitor resulted in reduced cell proliferation and enhanced apoptosis. Moreover, the modulator of apoptosis 1 (MOAP1) gene was identified as a novel target of miR-25. The ability of miR-25 to promote cell proliferation and block apoptosis is attributable to its effect on MOAP1 suppression. In addition, miR-25 antagomir significantly inhibited lung cancer growth via upregulation of MOAP1 in a mouse xenograft model. Collectively, these data demonstrate that miR-25 is an important biomarker for lung cancer, and miR-25 promotes cell proliferation and inhibits apoptosis in NSCLC cells by negatively regulating MOAP1 expression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Idoso , Animais , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/sangue , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer. To date, the prognosis of patients with LUAD remains dismal. METHODS: Three datasets were downloaded from the GEO database. Differentially expressed genes (DEGs) were obtained. FunRich was used to perform pathway enrichment analysis. Protein-protein interaction (PPI) networks were established and hub genes were obtained by Cytoscape software. GEPIA was utilized to conduct correlation and survival analysis. Upstream miRNAs of DEGs were predicted via miRNet database, and methylation status of promoters of DEGs was determined through UALCAN database. RESULTS: A total of 375 DEGs, including 105 and 270 up-regulated and down-regulated genes in LUAD, were commonly appeared in three datasets. These DEGs were significantly enriched in mesenchymal-to-epithelial transition (MET) and epithelial-to-mesenchymal transition (EMT). About 8 up-regulated and 5 down-regulated DEGs were commonly appeared in EMT/MET-related gene set and the top 50 hub gene set. Among the 13 genes, increased expression of KRT8 and KRT19 indicated unfavorable prognosis whereas high expression of DCN and CXCL12 suggested favorable prognosis in LUAD. Correlation analysis showed that KRT8 (DCN) expression was linked to KRT19 (CXCL12) expression. Further analysis displayed that KRT8 and KRT19 could jointly forecast poor prognosis in LUAD. About 42 and 2 potential miRNAs were predicted to target KRT8 and KRT19, respectively. Moreover, methylation level analysis demonstrated that KRT8 and KRT19 were significantly hypomethylated in LUAD compared with normal controls. CONCLUSIONS: All these findings suggest that KRT8 and KRT19 are hypomethylated and overexpressed in LUAD and associated with unfavorable prognosis.
Assuntos
Adenocarcinoma de Pulmão/mortalidade , Biomarcadores Tumorais/genética , Queratina-19/genética , Queratina-8/genética , Neoplasias Pulmonares/mortalidade , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Estudos de Casos e Controles , Quimiocina CXCL12/genética , Metilação de DNA , Conjuntos de Dados como Assunto , Decorina/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Prognóstico , Análise de Sobrevida , Regulação para CimaRESUMO
BACKGROUND: Recently, increasing evidence has uncovered the roles of mRNA-miRNA-lncRNA network in multiple human cancers. However, a systematic mRNA-miRNA-lncRNA network linked to pancreatic cancer prognosis is still absent. METHODS: Differentially expressed genes (DEGs) were first identified by mining GSE16515 and GSE15471 datasets. DAVID database was utilized to conduct functional enrichment analysis. Protein-protein interaction (PPI) network was built using STRING database, and hub genes were identified by Cytoscape plug-in CytoHubba. Upstream miRNAs and lncRNAs of mRNAs were predicted by miRTarBase and miRNet, respectively. Expression, survival and correlation analysis for genes, miRNAs and lncRNAs were performed via GEPIA, Kaplan-Meier plotter and starBase. RESULTS: 734 and 180 upregulated and downregulated significant DEGs were identified, respectively. Functional enrichment analysis revealed that they were significantly enriched in focal adhesion, pathways in cancer and metabolic pathways. According to node degree, hub genes in the PPI networks were screened, such as TGFB1 and ALB. Among the top 20 hub genes, 7 upregulated genes and 2 downregulated hub genes had significant prognostic values in pancreatic cancer. 33 miRNAs were predicted to target the 9 key genes. But only high expression of 8 miRNAs indicated favorable prognosis in pancreatic cancer. Then, 90 lncRNAs were predicted to potentially bind to the 8 miRNAs. SCAMP1, HCP5, MAL2 and LINC00511 were finally identified as key lncRNAs. By combination of results from expression, survival and correlation analysis demonstrated that MMP9/ITGB1-miR-29b-3p-HCP5 competing endogenous RNA (ceRNA) sub-network was linked to prognosis of pancreatic cancer. CONCLUSIONS: In a word, we established a novel mRNA-miRNA-lncRNA sub-network, among which each RNA may be utilized as a prognostic biomarker of pancreatic cancer.
Assuntos
MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Bases de Dados Factuais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , MicroRNAs/genética , Neoplasias Pancreáticas/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Regulação para CimaRESUMO
SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis. Mechanistic studies further revealed that PRMT5 (Protein arginine methyltransferase 5), responsible for catalyzing arginine methylation on histones, is a novel cofactor of SHARPIN. This finding provides the basis for further study of the crosstalk between protein ubiquitination and histone methylation. We further found that SHARPIN-PRMT5 is essential for the monomethylation of histones of chromatins at key metastasis-related genes, defining a new mechanism regulating cancer invasion. A novel MLL complex (ASH2 and WDR5) was implied in the link between histone arginine2 monomethylation (H3R2me1) and histone lysine4 trimethylation (H3K4me3) for the activation of metastasis-related genes. These novel findings establish a new epigenetic paradigm in which SHARPIN-PRMT5 has distinct roles in orchestrating chromatin environments for cancer-related genes via integrating signaling between H3R2me1 and H3K4me3.
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miR-145 has been implicated in the progression of breast cancer. Here, we report that its expression is decreased in breast cancer specimens and cell lines and that this low level of expression is associated with DNA methylation of its gene, MIR145. Methylation of MIR145 has previously been correlated with cell migration and invasion, both in vivo and in vitro. We found that demethylation of MIR145 reactivates miR-145 and contributes to the anti-cancer properties of 5-aza-2'-deoxyazacytidine (5-AzaC). Therefore, miR-145 is a potentially valuable biomarker for breast cancer.
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OBJECTIVE: To investigate the association between-1304T/G polymorphism in the promoter of MKK4 gene and the susceptibility in sporadic nasopharyngeal carcinoma. METHOD: MKK4-1304T/G genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 90 NPC cases and 30 healthy controls. RESULT: The number of nasopharyngeal carcinoma patients carrying with TG+GG genotype was much higher than those of controls (82.2% vs 66.7%, χ² =10.076, P < 0.05). Analysis showed that compared with the-1304TT genotype, -1304TG heterozygous reduced risk of nasopharyngeal carcinoma 0.56 fold (95% CI = 0.164-1.178, P < 0.01) and-1304GG lower 0.58 fold (95% CI = 0.126-1.381, P < 0.01), TG+ GG genotype variation risk of nasopharyngeal carcinoma decreased 0.72 fold (95% CI = 0.105-0.753, P < 0.01). CONCLUSION: MKK4 gene-1304TG genotype can reduce risk of nasopharyngeal carcinoma, and it may be an independent protection factor in sporadic nasopharyngeal carcinoma.
Assuntos
Predisposição Genética para Doença , MAP Quinase Quinase 4/genética , Neoplasias Nasofaríngeas/genética , Regiões Promotoras Genéticas , Carcinoma , Genótipo , Heterozigoto , Humanos , Carcinoma Nasofaríngeo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
Prostate cancer (PCa) is the second leading cause of cancer-related death in men. Androgen receptor has a key role in the initiation and progression of PCa. Currently, androgen deprivation therapy is the standard treatment for PCa patients due to its effective suppression of androgen receptor signaling. Even though androgen deprivation therapy shows its initial effectiveness on shrinking tumor size, it eventually fails to cure advanced PCa, which is determined by the occurrence of castration-resistance. In this review, we summarize the widely accepted mechanisms that account for castration-resistant PCa and discuss potential therapeutic targets.
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Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos/farmacologia , Humanos , Masculino , Terapia de Alvo Molecular , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Primary hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. However, the molecular pathogenesis of HCC is not well-understood, and the prognosis for patients with HCC remains very poor. METHODS: To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward development of novel therapeutic targets, we analyzed expression profiles HCCs and their corresponding noncancerous tissues by using bioinformatics method. RESULTS: In this paper, we report the identification of genes whose expression has been altered and the changed bio-pathways during hepatocarcinogenesis. Hepatoma cells infect intracellular and intercellular signal transduction through Focal adhesion and cause abnormal expression of important intracellular signaling pathway. In addition, it is worth mentioning that some small molecules still restored to the state similar to normal cells, such as bambuterol and lovastatin. This member gene set would serve as a pool of lead gene targets for the identification and development of novel diagnostic and therapeutic biomarkers to greatly improve the clinical management of HCC patients with different risks of recurrence after curative partial hepatectomy. CONCLUSIONS: The study has great significance for gene therapy and pharmacotherapy and provides a new treatment entry point and a potential new clinical drug for HCC patients.
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Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Análise por Conglomerados , Ontologia Genética , Humanos , Neoplasias Hepáticas/patologia , Transdução de Sinais/genéticaRESUMO
Telomeres are the end structures of chromosomes in mammalian cells; they play a pivotal role in maintaining the stability of the chromosome and become shorter with each cell division. However, several types of tumor cells express telomerase in very high levels to overcome this crisis and achieve the ability to proliferate endlessly. The telomerase inhibitors can partly inhibit tumor cell proliferation and promote apoptosis, but their roles are only limited. Tankyrase is a poly(ADP-ribose) polymerase which has synergistic effect on telomerase, and is expressed in lung cancer cells in high levels. In the present study, antisense oligonucleotides of telomerase (ashTERT) and tankyrase (asTANKS) were used as specific inhibitors to silence the expression of target genes in A549 human lung adenocarcinoma cells by transfection. The results showed that ashTERT and asTANKS suppressed the expression of telomerase and tankyrase significantly; both inhibited the activity of telomerase and the combination group achieved better effect, but only ashTERT shortened the length of telomeres, asTANKS did not. Further studies showed that ashTERT and asTANKS-promoted A549 apoptosis was not mediated by downregulation of the expression of the anti-apoptotic gene BCL-2 or upregulation of the expression of the pro-apoptotic gene BAX, but by adjusting the two isoforms proportion of myeloid cell leukemia-1 (MCL-1) which can interact with tankyrase directly. MCL-1short (MCL-1S), a pro-apoptotic gene, increased more than MCL-1Long (MCL-1L) which is an anti-apoptotic gene, leading to A549 cell apoptosis and a similar result was obtained in nude mice in vivo. The present study suggests that combination of the inhibitors of telomerase and tankyrase can be used as a strategy for the treatment of lung cancer in humans.
Assuntos
Adenocarcinoma/genética , Apoptose/genética , Neoplasias Pulmonares/genética , Tanquirases/genética , Telomerase/genética , Homeostase do Telômero/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Inativação Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Oligonucleotídeos Antissenso/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Tanquirases/metabolismo , Telomerase/metabolismo , TransfecçãoRESUMO
BACKGROUND & OBJECTIVE: Tankyrase (TANKS) regulates telomerase-mediated telomere elongation and plays an important role in cellular senescence and immortalization. This study was to determine the effect of tankyrase antisense oligonucleotide (asTANKS) combined human telomerase reverse transcriptase antisense oligonucleotide (ashTERT) on telomere dynamics in human lung adenocarcinoma A549 cells. METHODS: A549 cells were transfected with ashTERT, asTANKS, ashTERT combined asTANKS, and human telomerase reverse transcriptase sense oligonucleotide (shTERT), tankyrase sense oligonucleotide (sTANKS), or blank vector as control. The expression of hTERT mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Telomerase activity was detected by enzyme-linked immunosorbent assay-PCR (ELISA-PCR). Tankyrase activity was detected by Western blot. Telomere length was analyzed by quantitative fluorescence in situ hybridization (Q-FISH). Cell proliferation was measured by population doubling test. RESULTS: The mRNA level and telomerase activity of hTERT in A549 cells were strongly suppressed by ashTERT, but not by asTANKS; while tankyrase activity was significantly inhibited by asTANKS, not by ashTERT. Telomere length was significantly shorter in the cells treated with ashTERT combined asTANKS than in the cells treated with either ashTERT or asTANKS [(3.55+/-0.08) kb vs. (7.59+/-0.07) kb and (7.33+/-0.09) kb, t = 37.33, t = 32.50, P < 0.001]. The generational activity of the A549 cells continuously treated with ashTERT combined asTANKS was significantly weaker than those treated with either ashTERT or asTANKS [(24.53+/-0.40) population double times (PD) vs. (56.92+/-0.46) PD and (53.33+/-0.57) PD, t = 53.38, t = 43.39, P < 0.001]. CONCLUSIONS: The combination of ashTERT and asTANKS can enhance the efficacy of telomere shortening and hasten early tumor cellular crisis. Tankyrase might be a potential target of telomere-based molecular cancer therapy.