RESUMO
Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. In this study, we identified the functional expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer, as well as its association with breast cancer survival. Tissue microarray analysis using immunohistochemistry was constructed to identify the expression of pCHK2-Thr68 and pCDC25C-Ser216 in 292 female breast cancer patients. The relationship among protein expression, clinicopathological factors (e.g., human epidermal growth factor receptor 2 (HER 2), tumor size, tumor-node-metastasis (TNM) classification), and overall survival of the breast cancer tissues were analyzed using Pearson's χ-square (χ²) test, Fisher's exact test, multivariate logistic regression and Kaplan-Meier survival analysis. Significantly higher expressions of pCHK2-Thr68 and pCDC25C-Ser216 were observed in the nucleus of the breast cancer cells compared to the paracancerous tissue (pCHK2-Thr68, 20.38% vs. 0%; pCDC25C-Ser216, 82.26% vs. 24.24%). The expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer showed a positive linear correlation (p = 0.026). High expression of pCHK2-Thr68 was associated with decreased patient survival (p = 0.001), but was not an independent prognostic factor. Our results suggest that pCHK2-Thr68 and pCDC25C-Ser216 play important roles in breast cancer and may be potential treatment targets.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/biossíntese , Fosfatases cdc25/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Quinase do Ponto de Checagem 2/genética , Dano ao DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica/genética , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/genética , Metástase Linfática/patologia , Análise em Microsséries , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Fosfatases cdc25/genéticaRESUMO
The apurinic/apyrimidinic endonuclease 1 (APE1) plays important roles in the repair of DNA damage and adducts. However, previous case-control studies on the association between the APE1 Asp148Glu polymorphism and prostate cancer susceptibility have shown contradictory results, this meta-analysis was performed to draw a more precise estimation of the relationship. A total of seven case-control studies including 1,294 cases and 1,762 controls were included for analysis. In overall, no significant associations were found in all genetic models (GG vs. TT: OR = 1.16, 95 % CI 0.89-1.52; TG vs. TT: OR = 1.04, 95 % CI 0.81-1.35; the dominant model GG + TG vs. TT: OR = 1.12, 95 % CI 0.96-1.30; the recessive model GG vs. TG + TT: OR = 0.90, 95 % CI 0.77-1.04); in the subgroup by source of control, we found a significant association for the dominant model in Hospital-based subgroup (OR = 1.34, 95 % CI 1.08-1.68), no significant associations were found in other models in the subgroups. This meta-analysis suggested that the APE1 Asp148Glu polymorphism was a risk factor for prostate cancer susceptibility in Hospital-based population.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Intervalos de Confiança , Etnicidade/genética , Heterogeneidade Genética , Humanos , Masculino , Razão de Chances , Viés de PublicaçãoRESUMO
Wwox is a tumor suppressor that is frequently deleted or altered in several cancer types, including breast cancer. Previous studies have shown that ectopic expression of Wwox inhibits proliferation of breast cancer cells. However, the underlying mechanism remains unclear. To better understand the molecular mechanisms of Wwox function, we investigated novel partners of this protein. Utilizing the coimmunoprecipitation assay, we observed a physical association between Wwox and the Gli1 zinc-finger transcription factor involved in the hedgehog pathway. Our results further demonstrated that Wwox expression triggered redistribution of nuclear Gli1 to the cytoplasm. Additionally, ectopic expression of Wwox reduced Gli1 expression in vitro. Furthermore, Gli1 Blocks Wwox-induced breast cancer cell growth inhibition. These findings suggest a functional crosstalk between Wwox and hedgehog-GLI1 signaling pathway in tumorigenesis.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas Hedgehog/metabolismo , Oxirredutases/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Apoptose , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Oxirredutases/química , Oxirredutases/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Fatores de Transcrição/química , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW , Proteína GLI1 em Dedos de ZincoRESUMO
To date, epidemiological studies have assessed the association between CYP1A2-164 A/C polymorphism and colorectal cancer susceptibility. However, the results of these studies remained controversial. We aimed to examine the associations by conducting a meta-analysis of case-control studies. A total of 11 studies including 5,093 cases and 5,941 controls evaluated the association between the CYP1A2-164 A/C polymorphism and colorectal cancer susceptibility. No significantly associations were found in all genetic models (CC vs. AA: OR = 1.14, 95 % CI = 0.93-1.40; AC vs. AA: OR = 1.05, 95 % CI = 0.91-1.20; dominant model: OR = 1.08, 95 % CI = 0.95-1.24; recessive model: OR = 1.10, 95 % CI = 0.95-1.28). In the subgroup analysis by ethnicity or source of controls, there were still no significant associations detected in all genetic models. This meta-analysis suggested the CYP1A2-164 A/C polymorphism was not a risk factor for increasing colorectal cancer, further large and well-designed studies are needed to confirm these conclusions.
Assuntos
Neoplasias Colorretais/genética , Citocromo P-450 CYP1A2/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Genótipo , Humanos , Razão de Chances , Viés de PublicaçãoRESUMO
Published data regarding the association between the APE1 Asp148Glu polymorphism and breast cancer susceptibility showed inconclusive results. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, Elsevier, and Springer for relevant articles published before December 10. 2013. The strength of association between APE1 Asp148Glu polymorphism and breast cancer susceptibility was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95% CI) using the software Stata (version 10.0). A total of 7 case-control studies including 3,460 cases and 3,909 controls were included for analysis. Overall, no significant associations were found between the APE1 Asp148Glu polymorphism and breast cancer susceptibility for GG vs TT (OR = 1.00, 95% CI = 0.87-1.14); TG vs TT (OR = 1.06, 95% CI = 0.95-1.18); the dominant model GG + TG vs TT (OR = 1.04, 95% CI = 0.94-1.16) and the recessive model GG vs TG + TT (OR = 0.99, 95% CI = 0.88-1.11). In subgroup analysis, a significant association was found for TG vs TT in Asian subgroup (OR = 1.17, 95% CI = 1.00 ~ 1.36) and in population-based subgroup (OR = 1.18, 95% CI = 1.00 ~ 1.38). This meta-analysis suggested that the APE1 Asp148Glu polymorphism was a risk factor for breast cancer susceptibility among Asian population.
Assuntos
Neoplasias da Mama/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Predisposição Genética para Doença , Polimorfismo Genético , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Viés de PublicaçãoRESUMO
The XRCC1 Arg194Trp and Arg280His polymorphisms are likely to be implicated with the development of head and neck cancer. However, studies of association have been inconsistent. This meta-analysis of the available literature was performed to make a more precise estimation of the risk associated with these polymorphisms. A comprehensive literature search was conducted to identify all case-control studies of the XRCC1 Arg194Trp and Arg280His polymorphisms in head and neck cancer. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. A total of 20 eligible studies were selected for this meta-analysis, including 3,362 cases and 5,796 controls for the XRCC1 Arg194Trp polymorphism and 1,932 cases and 2,757 controls for the XRCC1 Arg280His polymorphism. Overall, no significant associations were found in all genetic models when the studies were pooled into the meta-analysis for the Arg194Trp and Arg280His polymorphisms. When stratified by ethnicity, significant associations were found for Arg194Trp polymorphism in CT vs CC (OR = 1.26, 95% CI = 1.05-1.52) and the recessive model (OR = 1.28, 95% CI = 1.07-1.53) in Asian population, and no significant associations were found in non-Asian population in all genetic models. This meta-analysis suggests that the XRCC1 Arg194Trp polymorphism is a risk factor for head and neck cancer in Asian populations.
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , Humanos , Prognóstico , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
The XPC Lys939Gln and Ala499Val polymorphisms were likely to be involved with the development of colorectal cancer. However, there had been inconsistent reports of association. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase and Web of Science for relevant articles with a time limit of December 2012. The strength of association between the XPC Lys939Gln and Ala499Val polymorphisms and colorectal cancer susceptibility were assessed by odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI). This meta-analysis including six case-control studies evaluated the associations between the two XPC polymorphisms (Lys939Gln, Ala499Val) and colorectal cancer susceptibility. For XPC Lys939Gln, no obvious associations were found for all genetic models [CC vs AA: OR (95 % CI) = 1.12 (0.94-1.32); CA vs AA: OR (95 % CI) = 1.08 (0.94-1.24); the dominant model: OR (95 % CI) = 1.09 (0.97-1.23); the recessive model: OR (95 % CI) = 1.07 (0.92-1.25)]. For XPC Ala499Val, no obvious associations were also not found for all genetic models [TT vs CC: OR (95 % CI) = 0.84 (0.65-1.10); CT vs CC: OR (95 % CI) = 1.00 (0.86-1.15); the dominant model: OR (95 % CI) = 0.98 (0.85-1.12); the recessive model: OR (95 % CI) = 0.87 (0.67-1.12)]. This meta-analysis suggested that both the XPC Lys939Gln and Ala499Val polymorphisms were not risk factors for increasing colorectal cancer.
Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Objective: This research aimed to assess the efficacy and safety of pembrolizumab (PBL) combined with albumin-bound paclitaxel (ab-Pac) and nedaplatin (NDP) for advanced esophageal squamous cell carcinoma (ESCC). Methods: A total of 47 ESCC patients were administered PBL or NDP on day 1 and ab-Pac on days 1 and 8, every 21 days for one cycle. Tumor and toxicities were evaluated every two cycles and every cycle, respectively. Results: The objective response rate was 68.1% and the disease control rate was 100%. The median follow-up was 16.7 months; median progression-free and overall survival were 12.6 and 19.9 months, respectively. Conclusion: The combination of PBL with ab-Pac and NDP proved to be an effective and safe treatment regimen for advanced ESCC.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Compostos Organoplatínicos , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Paclitaxel Ligado a Albumina/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Resultado do Tratamento , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Immune cells have the potential to control the growth of tumor. However, this effect could be offset by immunosuppression associated with an increased production of reactive oxygen species. Multiple studies indicate that the antitumor effect of immune cells is correlated with their antioxidant capacity. This review discusses the role of reactive oxygen species in the tumor microenvironment by describing their distinct effects on different immune cells, including myeloid-derived suppressor cells, regulatory T cells, tumor-associated macrophages, cytotoxic T lymphocytes, natural killer cells, and dendritic cells. In the end, we conclude with the prospect of treatment for cancer by targeting antioxidant defense in immune cells.
Assuntos
Sistema Imunitário/metabolismo , Neoplasias/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/patologia , Imunossupressores/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Microambiente TumoralRESUMO
Pancreatic mucinous cystadenocarcinoma (MCC) is a rare malignant tumor, with a limited number of studies. The present study aimed to investigate the function and mechanism of microRNA (miR)2245p on proliferation, migration and invasion of MCC of the pancreas. Reverse transcriptionquantitative PCR was used to explorethe expression of miR2245p and the PTEN gene. MTT, wound healing, Transwell and tumorigenesis assays were conducted to investigate the proliferation, migration and invasion of MCC1 cells in vitro and in vivo. Western blot analysis was employed to test the protein expression of PTEN. The target gene of miR2245p was assessed and verified by luciferase assay. miR2245p expression was notably higher, while PTEN expression was lower, in MCC1 cells compared with normal tissues and cells. Overexpression of miR2245p promoted the proliferation, migration and invasion of MCC and knockdown of miR2245p inhibited these functions. Bioinformatics analysis and luciferase assay indicated that PTEN was the direct target gene of miR2245p. The negative correlation between miR2245p and PTEN was confirmed both in vitro and in vivo. PTEN reversed the effects of miR2245p on proliferation, migration and invasion of MCC1 cells. The present study revealed for the first time, to the best of the authors' knowledge, that miR2245p was highly expressed and served an oncogenic role in MCC. miR2245p not only regulated the proliferation, migration and invasion of pancreatic MCC but may also be a potential therapeutic target for MCC.
Assuntos
Cistadenocarcinoma Mucinoso/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias Pancreáticas/genética , Idoso , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cistadenocarcinoma Mucinoso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/patologiaRESUMO
The prognosis of invasive pancreatic mucinous cystadenocarcinoma (MCC) is poor, and the molecular mechanism underlying its development remains unclear. The present study aimed to explore the potential role of autophagy in pancreatic MCC. The results demonstrated an increase in autophagy signaling in pancreatic MCC tissues and the MCC1 cell line compared with adjacent tissues and normal human pancreatic ductal epithelium (HPDE) cells. In addition, abnormal autophagy activation facilitated the migration and invasion of MCC1 cells. MicroRNA (miR)-224-5p expression levels were significantly higher in MCC1 cells compared with those in HPDE cells. Treatment with rapamycin further demonstrated that high levels of autophagy elevated miR-224-5p expression in MCC1 cells in a time-dependent manner. BCL2 was identified as a downstream target gene of miR-224-5p, which binds to the 3'-untranslated region of BCL2. In addition, the results of the present study demonstrated that BCL2 knockdown reversed the inhibition of autophagy mediated by the miR-224-5p inhibitor. To the best of our knowledge, this is the first study to evaluate the role of autophagy in pancreatic MCC. Thus, these results suggested that autophagy may be hyperactivated in pancreatic MCC. In addition, the present study identified a positive feedback loop between autophagy signaling and miR-224-5p, which may promote the aggressive migration and invasion of MCC1. These results may provide a new insight into the relationship between autophagy and tumor metastasis in pancreatic MCC.
RESUMO
Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, which is characterized by the negative form of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). TNBC accounts for ~15% of all breast cancer forms, and often leads to high mortality and poor prognosis. Structural maintenance of chromosome 1 (SMC1) is a subunit of the cohesion protein complex. Brachyury is a protein that is encoded by the T gene in humans, which is a transcription factor within the T-box complex of genes. Epithelial-mesenchymal transition (EMT) is a ubiquitous process in the body, and in particular, induces metastasis and the proliferation of cancer cells. In the present study, we found that SMC1 expression in TNBC tissues exceeded its expression in adjacent non-tumor tissues. Similarly, the expression of SMC1 in TNBC cell lines (hs578T and HCC1937) was found to be higher than in MCF10a and MCF7 cells. Subsequently, SMC1 was overexpressed and silenced in hs578T and HCC1937 cells through plasmid and siRNA transfection, respectively. The results showed that the high expression of SMC1 often promoted EMT, accompanied by the enhanced expression of Brachyury. Besides, upregulated expression of Brachyury through plasmid transfection also significantly improved the level of EMT, which further indicated that SMC1 increased EMT in TNBC through the induction of Brachyury expression. Taken together, these results contributed to a better understanding of the pathogenesis of TNBC, which also provided an experimental basis for the prevention, diagnosis and treatment of TNBC.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Transição Epitelial-Mesenquimal , Proteínas Fetais/metabolismo , Proteínas com Domínio T/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Myosin VI (MYO6) is a unique member of the myosin superfamily. Although it has been reported to participate in human cancer progression, the role of MYO6 in gastric cancer remains unclear. In this study, we found the expression of MYO6 gene was higher in gastric cancer tissues than in the normal tissues by Oncomine database mining and affects patient overall survival using the Kaplan-Meier plotter online analysis. Additionally, the expression levels of MYO6 were widely expressed in gastric cancer cells by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and western blot assay. Then knockdown of MYO6 significantly suppressed the proliferation and colony formation abilities of AGS and MGC80-3 cells. Moreover, cell cycle analysis showed that inhibition of MYO6 induced cell cycle arrested in G0/G1 phase in AGS and MGC80-3 cells. Further analysis showed knockdown of MYO6 downregulated cell-cycle activators cyclin A and cyclin D1 and upregulated cell-cycle inhibitor p21, as determined by qRT-PCR and western blot analysis in MGC80-3 cells. Meanwhile, MYO6 inhibition significantly induced apoptosis in AGS and MGC80-3 cells. Also, knockdown of MYO6 increased the expression of apoptosis-related proteins Bax and cleaved Caspase-3, and decreased Bcl-2 expression by western blot analysis in MGC80-3 cells. In addition, MYO6 knockdown also inhibited cell migration ability in MGC80-3 cells. Taken together, our study indicates that MYO6 may play an important role in gastric cancer tumorigenesis and may serve as a potential therapeutic target in human gastric cancer.
Assuntos
Fase G1 , Regulação Neoplásica da Expressão Gênica , Cadeias Pesadas de Miosina/metabolismo , Fase de Repouso do Ciclo Celular , Neoplasias Gástricas/metabolismo , Regulação para Cima , Caspase 3/biossíntese , Caspase 3/genética , Linhagem Celular Tumoral , Ciclina A/biossíntese , Ciclina A/genética , Ciclina D1/biossíntese , Ciclina D1/genética , Técnicas de Silenciamento de Genes , Humanos , Cadeias Pesadas de Miosina/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genéticaRESUMO
The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.
Assuntos
Antieméticos/administração & dosagem , Antieméticos/farmacocinética , Bulbo Olfatório/metabolismo , Escopolamina/administração & dosagem , Escopolamina/farmacocinética , Vestíbulo do Labirinto/metabolismo , Administração Intranasal , Animais , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Microdiálise , Mucosa Olfatória/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Tamoxifen is effective for treating estrogen receptor-alpha (ERα)-positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. In the present study, we determine the underlying roles of Brachyury in tamoxifen resistance. Loss- and gain-of-function assay are utilized to confirm the oncogenic roles of Brachyury in breast cancer. Compared with the normal MCF10A cells, Brachyury is commonly overexpressed in breast cancer cell lines. Knockdown of Brachyury inhibits tamoxifen resistance, whereas overexpression of Brachyury enhances tamoxifen resistance as demonstrated increased cell viability and reduced cell apoptosis. Mechanistically, we demonstrate for the first time that Brachyury mediates tamoxifen resistance by regulating Sirtuin-1 (SIRT1). Collectively, our data, as a proof of principle, indicate that Brachyury is a candidate marker for predicting the clinical efficacy of tamoxifen and targeting SIRT1 could overcome resistance to tamoxifen in breast cancer cells.
Assuntos
Biomarcadores Tumorais/biossíntese , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas Fetais/biossíntese , Marcação de Genes/métodos , Sirtuína 1/biossíntese , Proteínas com Domínio T/biossíntese , Tamoxifeno/farmacologia , Biomarcadores Tumorais/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Proteínas Fetais/genética , Humanos , Células MCF-7 , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Proteínas com Domínio T/genéticaRESUMO
Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is a tumor suppressor that frequently down-regulated in cancers, especially breast cancer. Here, we provide both supporting and contradicting evidences about the expression pattern and function of FBP1 in breast cancer. Data mining of Oncomine database showed that FBP1 is commonly up-regulated in tumor tissues compared with non-tumor tissues regardless of histological type. Analysis of a large-scale cohort derived from Kaplan-Meier Plotter showed that lower FBP1 expression associated with poor clinical outcome. Genetic silencing of FBP1 reduced aerobic glycolysis and the malignant potential of breast cancer cells. Gene set enrichment analysis (GSEA) of the expression profiles of breast cancer cells (n=59) revealed that cells exhibiting high expression of FBP1 had a lower activity of Wnt/ß-Catenin pathway. FBP1 down-regulation enhanced the activity of Wnt/ß-Catenin pathway and increased the level of its downstream targets, including c-Myc and MMP7. Collectively, our findings indicate that elevated FBP1 is a critical modulator in breast cancer progression by altering glucose metabolism and the activity of Wnt/ß-Catenin pathway.
Assuntos
Neoplasias da Mama/enzimologia , Frutose-Bifosfatase/metabolismo , Via de Sinalização Wnt , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Biologia Computacional , Bases de Dados Genéticas , Feminino , Frutose-Bifosfatase/genética , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Fatores de Tempo , Transfecção , Regulação para CimaRESUMO
The aims of the present study were to investigate the effect of overexpressed exogenous glutathione S-transferase π 1 (GSTP1) gene on the radiosensitivity of the HeLa human cervical cancer cell line and conduct a preliminarily investigation into the underlying mechanisms of the effect. The full-length sequence of human GSTP1 was obtained by performing a polymerase chain reaction (PCR) using primers based on the GenBank sequence of GSTP1. Subsequently, the gene was cloned into a recombinant eukaryotic expression plasmid, and the resulting construct was confirmed by restriction analysis and DNA sequencing. A HeLa cell line that was stably expressing high levels of GSTP1 was obtained through stable transfection of the constructed plasmids using lipofectamine and screening for G418 resistance, as demonstrated by reverse transcription-PCR. Using the transfected HeLa cells, a colony formation assay was conducted to detect the influence of GSTP1 overexpression on the cell radiosensitivity. Furthermore, flow cytometry was used to investigate the effect of GSTP1 overexpression on cell cycle progression, with the protein expression levels of the cell cycle regulating factor cyclin B1 detected using western blot analysis. Colony formation and G2/M phase arrest in the GSTP1-expressing cells were significantly increased compared with the control group (P<0.01). In addition, the expression of cyclin B1 was significantly reduced in the GSTP1-expressing cells. These results demonstrated that increased expression of GSTP1 inhibits radiosensitivity in HeLa cells. The mechanism underlying this effect may be associated with the ability of the GSTP1 protein to reduce cyclin B1 expression, resulting in significant G2/M phase arrest.
RESUMO
Published data regarding the association between the XRCC1 Arg399Gln polymorphism and head and neck cancer (HNC) susceptibility showed inconsistent results. This meta-analysis of eligible literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase, and Web of Science with a time limit of Oct 28, 2013. Summary odds ratios (ORs) with 95% CIs were used to assess the strength of association between XRCC1 Arg399Gln polymorphism and HNC susceptibility using random-effect model. A total of 27 case-control studies including 5942 cases and 9041 controls were included for analysis. Meta-analysis of total studies showed that the XRCC1 Arg399Gln variant carriers were not susceptible to HNC (AA vs. GG: OR=0.92, 95% CI=0.77-1.11; AG vs. GG: OR=1.05, 95% CI=0.76-1.44; the dominant model AA+AG vs. GG: OR=1.00, 95% CI=0.78-1.29; the recessive model AA vs. AG+GG: OR=0.91, 95% CI=0.71-1.16). Further, subgroup analyses by ethnicity and source of controls did not identify any significant associations of XRCC1 Arg399Gln polymorphism with head and neck susceptibility in any populations. Our meta-analysis suggested that the XRCC1 Arg399Gln polymorphism was not a risk factor for HNC susceptibility.
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Substituição de Aminoácidos , Estudos de Casos e Controles , Humanos , Polimorfismo Genético , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
PURPOSE: Constitutive activation of JAK/STAT pathway is observed in various solid tumors and hematological malignancies. SOCS3 acts as a key negative regulator of JAK/STAT pathway and represents one of the candidate tumor suppressor genes. In the current study, we aimed to evaluate SOCS3 expression in breast carcinoma and to explore the prognostic significance of SOCS3. METHODS: The expression of SOCS3 was measured by Western blot and immunohistochemistry in breast carcinoma cells and a large cohort of tissue microarray, respectively. RESULTS: Among 367 human primary breast tumors, SOCS3 protein was detected in 103 patients. Deficient SOCS3 expression correlated significantly with lymph node metastasis (P = 0.003), blood vessel invasion (P = 0.029), VEGF (P = 0.001) and Ki-67 (P = 0.027). Univariate and multivariate analyses revealed that SOCS3 expression was an independent prognostic factor for disease-free survival (P < 0.0001). A positive SOCS3 protein expression correlated significantly with a low pSTAT3 protein expression in breast carcinoma (P = 0.015). The patients with a SOCS3 (+)/pSTAT3 (-) phenotype had a better prognosis than any other combination (DFI: P < 0.0001, BCSS: P = 0.013). CONCLUSIONS: Deficient expression of SOCS3 is associated with an aggressive phenotype and portends a poor clinical outcome in breast carcinoma.
Assuntos
Neoplasias da Mama/etiologia , Recidiva Local de Neoplasia/etiologia , Proteínas Supressoras da Sinalização de Citocina/análise , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de CitocinasRESUMO
OBJECTIVES: To investigate the expression of P300/CBP-associated factor (PCAF) protein in intestinal type gastric cancer (ITGC); analyze the relationship between the expression of PCAF protein and the clinical pathological characteristics of patients; explore the effects of PCAF protein on biological behaviors of ITGC. RESULTS: The expression of PCAF was markedly down-regulated in GC cell lines and ITGC tissues. PCAF was able to suppress tumorigenicity of GC cells both in vitro and in vivo, including colony formation in soft agar and tumor formation in nude mice. PCAF could also inhibit GC cells entering S phase from G1 phase. Statistical analysis displayed a significant correlation in PCAF expression with the gastric wall invasion, tumor size, TNM stage, p21, pRb (P<0.001) and PCNA (P<0.01) in ITGC specimens. A reduced PCAF protein expression correlated significantly with a mutant type p53 protein expression (P<0.01). Univariate analysis indicated that the patients demonstrating the high-PCAF/wild type p53 expression have a significantly (P<0.0001) better overall survival (OS), while multivariate analysis indicated that the location, lymph node metastasis, PCAF/p53 (P<0.0001), gastric wall invasion (P=0.001) and PCNA (P=0.018) are independently significant prognostic factors for OS. METHODS: Immunohistochemistry was performed to evaluate the expression of PCAF in a large subset containing 406 ITGC samples. Eukaryotic expression plasmid pcDNA3.1/PCAF was constructed and transfected into the human gastric cancer cell line SGC-7901 and protein expression was detected by Western blot. The proliferation and cell cycle of gastric cancer cells were evaluated by MTT assay and flow cytometry. Tumor growth in nude mice was used to access the tumorigenicity of gastric cancer cells. Apoptosis cells were detected by TUNEL staining. CONCLUSION: Reduced expression of PCAF plays an important role in the development of ITGC and correlates with a poor clinical outcome.