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1.
Biomed Res Int ; 2021: 4873678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337013

RESUMO

LIHC (liver hepatocellular carcinoma) mostly occurs in patients with chronic liver disease. It is primarily induced by a vicious cycle of liver injury, inflammation, and regeneration that usually last for decades. The G protein nucleolar 2 (GNL2), as a protein-encoding gene, is also known as NGP1, Nog2, Nug2, Ngp-1, and HUMAUANTIG. Few reports are shown towards the specific biological function of GNL2. Meanwhile, it is still unclear whether it is related to the pathogenesis of carcinoma up to date. Here, our study attempts to validate the role and function of GNL2 in LIHC via multiple databases and functional assays. After analysis of gene expression profile from The Cancer Genome Atlas (TCGA) database, GNL2 was largely heightened in LIHC, and its overexpression displayed a close relationship with different stages and poor prognosis of carcinoma. After enrichment analysis, the data revealed that the genes coexpressed with GNL2 probably participated in ribosome biosynthesis which was essential for unrestricted growth of carcinoma. Cell functional assays presented that GNL2 knockdown by siRNA in LIHC cells MHCC97-H and SMCC-7721 greatly reduced cell proliferation, migration, and invasion ability. All in all, these findings capitulated that GNL2 could be a promising treatment target and prognosis biomarker for LIHC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Proteínas de Ligação ao GTP/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Proteínas de Ligação ao GTP/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , Reprodutibilidade dos Testes , Transdução de Sinais/genética
2.
Food Funct ; 12(10): 4644-4653, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33912875

RESUMO

Chronic diseases, such as obesity, cause great harm to human health. Conventional drugs have promising therapeutic effects but also cause significant side effects. Functional foods are an excellent therapeutic alternative to pharmaceuticals, as they have fewer side effects. However, screening for active ingredients in natural foods is difficult. In this study, a novel pancreatic lipase inhibitor screening strategy, guided by the drug molecule orlistat, was combined with experimental verification. Twenty compounds from natural foods were evaluated based on the characteristics of orlistat interaction with pancreatic lipase. The characteristics of 13 molecules were comparable to those of orlistat. The pancreatic lipase inhibition rates of curcumin and sinensetin were 82.42 ± 0.50% and 81.07 ± 2.05%, respectively, and their IC50 values were 0.971 mM and 0.526 mM, respectively; both the inhibition rates as well as IC50 values were similar to those of orlistat. Curcumin and sinensetin prevented weight gain in mice by 69.17% and 52.29%, respectively, compared to orlistat. Curcumin and sinensetin did not cause significant organ damage in vivo, but significantly reduced the contents of triglycerides and cholesterol in blood and lipids in the liver, protecting liver function. Furthermore, 57 328 molecules in the Chinese Natural Product Database library were screened, and 20 potentially active molecules, found to be highly efficient in our study, were selected. Thus, we successfully established an efficient and accurate strategy for screening active ingredients in natural foods under the guidance of a drug molecule, providing valuable insights for functional food development.

3.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33593829

RESUMO

BACKGROUND: The activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored. METHODS: Monocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed. RESULTS: TAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions. CONCLUSIONS: Our data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.

4.
Oncol Lett ; 20(6): 312, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33093921

RESUMO

M2 isomer of pyruvate kinase (PKM2), a key enzyme in aerobic glycolysis, is closely related to cancer development and progression. Suppression of PKM2 exhibits synergistic effects with docetaxel in lung cancer, but the therapeutic potential in colorectal cancer (CRC) is unclear. The aim of the present study was to explore the synergic effects and mechanism of knocking down PKM2 combined with oxaliplatin (a chemosensitizer) treatment in two CRC cell lines (HCT116 and DLD1). The PKM2 gene was initially knocked down using small interfering (si)RNAs (si155 and si156). Subsequently, the effects of PKM2-siRNAs and oxaliplatin, on CRC cells were determined using MTS, cell cycle analysis and apoptosis assays. The mechanism of targeting PKM2 was explored by detecting glucose uptake, lactate secretion fluxes, and the levels of glucose-6-phosphate dehydrogenase (G6PD) mRNA, glutathione (GSH) and reactive oxygen species (ROS). Cell viability in the experimental groups (PKM2-siRNAs, oxaliplatin, PKM2-siRNAs + oxaliplatin) was significantly reduced compared with the control group, and combination treatments (PKM2-siRNAs + oxaliplatin) were more effective than single treatments (PKM2-siRNAs and oxaliplatin only groups). Similar results were observed with the apoptosis assay. The combination groups showed synergistic effects compared with both single treatment groups. Furthermore, glucose uptake and lactate secretion and mRNA levels of G6PD and PKM2 were decreased after PKM2 knockdown in the PKM2-siRNAs and PKM2-siRNAs + oxaliplatin groups. The GSH levels in the PKM2-siRNAs group was significantly lower compared with the negative control group. The ROS levels in the PKM2-siRNAs groups were also significantly increased. The combination of PKM2-siRNAs and oxaliplatin had synergistic effects on CRC cells (HCT116 and DLD1). PKM2 silencing may alter energy metabolism in cancer cells and initiate ROS-induced apoptosis after downregulation of the pentose phosphate pathway by PKM2-siRNAs.

5.
J Agric Food Chem ; 68(18): 5129-5137, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32297517

RESUMO

Prolyl endopeptidases (PEPs) hydrolyze proteins to yield bioactive peptides and are effective in the treatment of celiac disease. However, the catalytic efficiency of PEPs still has the potential to be improved, which could further strengthen their industrial and therapeutic applications. Herein, a novel rational design strategy based on a "near-attack conformation" of the catalytic state of PEP was adopted. Constrained dynamic simulations were applied, followed by the virtual screening of potentially favorable mutants according to their binding free energy. We redesigned Sphaerobacter thermophiles PEP with high-temperature activity/stability, a wide range of pH stabilities, and high proline specificity. As a result, the kcat value of two PEP mutants (I462W and Q560Y) increased by 208.2 and 150.1%, respectively, and the kcat/KM increased by 32.7 and 6.3%, respectively. These data revealed that the PEP mutants had improved catalytic efficiency and that our strategy can be applied for enzyme engineering.


Assuntos
Proteínas de Bactérias/química , Chloroflexi/enzimologia , Prolil Oligopeptidases/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biocatálise , Chloroflexi/química , Chloroflexi/genética , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Cinética , Prolil Oligopeptidases/genética , Prolil Oligopeptidases/metabolismo , Conformação Proteica , Especificidade por Substrato
6.
Ecol Evol ; 9(22): 12846-12857, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31788219

RESUMO

Background and aims: Soil respiration is the second-largest terrestrial carbon (C) flux, and soil temperature and soil moisture are the main drivers of temporal variation in soil respiration and its components. Here, we quantified the contribution of soil temperature, soil moisture, and their intersection on the variation in soil respiration and its components of the evergreen broad-leaved forests (EBF), mixed evergreen and deciduous broad-leaved forests (MF), deciduous broad-leaved forests (DBF), and subalpine coniferous forests (CF) along an elevation gradient. Methods: We measured soil respiration of four types of forests along the elevation gradient in Shennongjia, Hubei China based on the trenching experiments. We parameterized the relationships between soil respiration and soil temperature, soil moisture, and quantified the intersection of temperature and moisture on soil respiration and its components. Results: Total soil respiration (R S), heterotrophic respiration (R H), and autotrophic respiration (R A) were significantly correlated with soil temperature in all four forests. The Q 10 value of soil respiration significantly differed among the four types of forest, and the Q 10 was 3.06 for EBF, 3.75 for MF, 4.05 for DBF, and 4.49 for CF, respectively. The soil temperature explained 62%-81% of the variation in respiration, while soil temperature and soil moisture together explained 91%-97% of soil respiration variation for the four types of forests. The variation from the intersection of soil temperature and moisture were 12.1%-25.0% in RS, 1.0%-7.0% in R H, and 17.1%-19.6% in R A, respectively. Conclusions: Our results show that the temperature sensitivity (Q 10) of soil respiration increased with elevation. The intersection between soil temperature and soil moisture had strong effects on soil respiration, especially in R H. We demonstrated that the intersection effects between soil temperature and soil moisture on soil respiration were essential to understand the response of soil respiration and its components to climate change.

7.
Oxid Med Cell Longev ; 2019: 4010764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737170

RESUMO

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.


Assuntos
Diabetes Mellitus Tipo 2/genética , Hiperglicemia/genética , Células Secretoras de Insulina/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Células Secretoras de Insulina/fisiologia , Estresse Oxidativo/genética , Ratos , Sirtuína 1/genética , Sirtuína 1/metabolismo
8.
Mol Cancer ; 18(1): 145, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623628

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have recently been identified as potential functional modulators of the cellular physiology processes. The study aims to uncover the potential clinical value and driving molecular mechanisms of circRNAs in gallbladder cancer (GBC). PATIENTS AND METHODS: We performed RNA sequencing from four GBC and paired adjacent normal tissues to analyze the circRNA candidates. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to measure the circFOXP1 expression from 40 patient tissue samples. Short hairpin RNA mediated knockdown or exogenous expression of circFOXP1 combined with in vitro and in vivo assays were performed to prove the functional significance of circFOXP1. Double luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were also performed. RESULTS: By performing RNA sequencing from GBC and paired adjacent normal tissues to analyze the circRNA candidates, we identified that circFOXP1 (hsa_circ_0008234) expression was significantly upregulated in GBC tissues and positively associated with lymph node metastasis, advanced TNM stage and poor prognosis in patients. Short hairpin RNA mediated knockdown or exogenous expression of circFOXP1 combined with in vitro assays demonstrated that circFOXP1 has pleiotropic effects, including promotion of cell proliferation, migration, invasion, and inhibition of cell apoptosis in GBC. In vivo, circFOXP1 promoted tumor growth. Mechanistically, double luciferase reporter, RNA immunoprecipitation (RIP) and biotin-labeled RNA pull-down assays clarified that circFOXP1 interacted with PTBP1 that could bind to the 3'UTR region and coding region (CDS) of enzyme pyruvate kinase, liver and RBC (PKLR) mRNA (UCUU binding bites) to protect PKLR mRNA from decay. Additionally, circFOXP1 acted as the sponge of miR-370 to regulate PKLR, resulting in promoting Warburg effect in GBC progression. CONCLUSIONS: These results demonstrated that circFOXP1 serve as a prognostic biomarker and critical regulator in GBC progression and Warburg effect, suggesting a potential target for GBC treatment.


Assuntos
Metabolismo Energético , Fatores de Transcrição Forkhead/genética , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica , Piruvato Quinase/genética , RNA Circular , Proteínas Repressoras/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Perfilação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
9.
Cancer Med ; 8(14): 6315-6325, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31486298

RESUMO

Endoscopic resection (ER) has been increasingly performed in the treatment of early gastric cancer (GC). However, lymph node metastasis (LNM) can cause treatment failure with ER, especially in T1b patients. Here, we attempted to develop a miRNA-based classifier to detect LNM in T1b patients. Based on high-throughput data from The Cancer Genome Atlas, we identified 20 miRNAs whose expression significantly changed in T1-2 GC with LNM vs T1-2 GC without LNM. We then developed a miRNA signature to predict LNM of T1b GC using the LASSO model and backward step wise elimination approach in a training cohort. Furthermore, the predictive accuracy of this classifier was validated in both an internal testing group of 63 patients and an external independent group of 114 patients. This systematic and comprehensive in silico study identified a 7-miRNA signature with an area under the receiver operating characteristic curve (AUROC) value of 0.843 in T1-2 GC and 0.911 in T1 EGC. The backward elimination was further used to develop a 4-miRNA (miR-153-3p, miR-708, miR-940 and miR-375) risk-stratification model in the training cohort with an AUROC value of 0.898 in cohort 2. When pathologic results were used as a reference, the risk model yielded AUROC values of 0.829 and 0.792 in two cohorts of endoscopic biopsy specimens. This novel miRNA-LNM classifier works better than the currently used pathologic criteria of ER in T1b EGC. This classifier could individualize the management of T1b patients and facilitate treatment decisions.


Assuntos
Biomarcadores Tumorais , MicroRNAs , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Biópsia , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Curva ROC , Reprodutibilidade dos Testes , Neoplasias Gástricas/diagnóstico , Transcriptoma
10.
ANZ J Surg ; 89(4): 377-382, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30854753

RESUMO

BACKGROUND: The systemic inflammation score (SIS), as calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been demonstrated to be a prognostic marker in cancer. The present study intended to investigate the prognostic role of SIS in gastric cancer patients after curative gastrectomy in comparison with other prognostic markers. METHODS: Preoperative SIS was retrospectively calculated in patients who underwent curative gastrectomy between 2007 and 2011 in Fudan University Shanghai Cancer Center. The prognostic accuracy of each score was compared utilizing time-dependent receiver operating characteristics analysis. RESULTS: The higher SIS score was associated with older age, larger tumour size, a more advanced tumour-nodes-metastasis stage and lymph node status, deeper tumour invasion, the presence of lymphovascular invasion and a poorer overall survival and disease-free survival. In time-dependent receiver operating characteristics analysis, the SIS had a higher area under the curve for the prediction of 5-year overall survival than the neutrophil lymphocyte ratio. The SIS maintained the predictive accuracy superiority throughout the observation period. CONCLUSION: The SIS is a useful prognostic marker in gastric cancer patients after curative gastrectomy.


Assuntos
Gastrectomia/mortalidade , Inflamação/sangue , Neoplasias Gástricas/sangue , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , China/epidemiologia , Intervalo Livre de Doença , Feminino , Gastrectomia/métodos , Humanos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Neutrófilos/citologia , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia
11.
Dig Surg ; 36(5): 433-442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30300879

RESUMO

BACKGROUND: It is known that inflammation promotes cancer development. However, a few studies have evaluated the prognostic significance of inflammatory biomarkers in gastric cancer (GC). METHODS: In this study, 2,334 patients who underwent gastrectomy for GC at Fudan University Shanghai Cancer Center between 2003 and 2007 were retrospectively analyzed, and 1,227 patients were found to be eligible. The preoperative serum neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) levels were analyzed. A nomogram was constructed with the Cox proportional hazards regression model in the training set (n = 818) to predict the probability of overall survival (OS) and disease-free survival (DFS). The predictive accuracy and discriminative ability were determined using the concordance index (C-index) and calibration curve. RESULTS: We found that lower AGR and LMR values were correlated with decreased OS, lower LMR values, and higher NLR values with a decreased DFS. Other significant factors were included to construct the nomogram. The discriminative ability of the nomogram was higher than that of the eighth American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system (0.746 for TNM v.s. 0.654 for the nomogram, p < 0.001). CONCLUSIONS: The nomogram yielded a more accurate prognostic prediction in GC patients after gastrectomy, suggesting great clinical value.


Assuntos
Inflamação/sangue , Monócitos , Neutrófilos , Nomogramas , Neoplasias Gástricas/sangue , Adulto , Idoso , Biomarcadores/sangue , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Albumina Sérica/metabolismo , Soroglobulinas/metabolismo , Neoplasias Gástricas/patologia , Taxa de Sobrevida
12.
Mol Ther ; 26(11): 2658-2668, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30274785

RESUMO

Long noncoding RNAs (lncRNAs) have been demonstrated to play a role in carcinogenesis, but their mechanisms of function remain elusive. We explored the mechanisms of the oncogenic role of GCAWKR in gastric cancer (GC) using human tissues and cell lines. The in situ hybridization analysis was utilized to determine GCAWKR levels in samples from 42 GC patients and real-time qPCR in tissues from 123 patients. The GCAWKR levels were modulated in GC cell lines, and relevant biological and molecular analyses were performed. Levels of the GCAWKR were upregulated in GC tissues compared with normal tissues and associated with tumor size, lymph node metastasis, TNM stage, and patient outcomes. GCAWKR affected cell proliferation and cell invasion in multiple GC models. Mechanistically, GCAWKR bound WDR5 and KAT2A and acted as a molecular scaffold of WDR5/KAT2A complexes, modulating the affinity for WDR5/KAT2A complexes in the target gene's promoter region. Thus, our data defined a mechanism of lncRNA-mediated carcinogenesis in GC, suggesting new therapeutic targets in GC.


Assuntos
Histona Acetiltransferases/genética , Histona-Lisina N-Metiltransferase/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Metástase Linfática , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/patologia
13.
Onco Targets Ther ; 11: 3065-3074, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29872318

RESUMO

Introduction: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are frequently deregulated in several human malignancies, including gastric cancer (GC). NOX-derived reactive oxygen species have been reported to contribute to gastric carcinogenesis and cancer progression. However, the expression and prognostic role of individual NOX in GC patients remain elusive. Methods and materials: We investigated genetic alteration and mRNA expression of NOX family in GC patients via the cBioPortal, Human Protein Atlas, and Oncomine databases. Furthermore, we evaluated prognostic value of distinct NOX in GC patients through "The Kaplan-Meier plotter" database. Results: Our analysis demonstrated that mRNA deregulation of NOX genes was common alteration in GC patients. Compared with normal tissues, NOX1/2/4 mRNA expression levels in GC tissues were higher, while NOX5 and DUOX1/2 expression levels were lower. Importantly, our results indicated that high mRNA expression of NOX2 was associated with better overall survival whereas NOX4 and DUOX1 were correlated with worse overall survival in all GC patients, particularly in intestinal-type GC patients. In addition, our data also shed light on the diverse roles of individual NOX members in GC patients with different clinicopathological features, including human epidermal growth factor receptor 2 status, clinical stages, pathological grades, and different choices of treatments of GC patients. Conclusion: These findings suggest that individual NOX family genes, especially NOX2/4, and DUOX1, are potential prognostic markers in GC and implicate that the use of NOX inhibitor targeting NOX4 and DUOX1 may be an effective strategy for GC therapy.

14.
Onco Targets Ther ; 11: 2169-2176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713185

RESUMO

Background: The correlations between lipid profile (lipid molecules and their derivative indexes) and clinical outcome have been widely testified in many carcinomas, but its prognostic value remains unknown in gastric cancer (GC). Our purpose in the study was to comprehensively evaluate the clinical significance of lipid profile in GC. Methods: We retrospectively collected clinical information of 1,201 GC patients who received surgery at Sun Yat-sen University Cancer Center from 2005 to 2010. Kaplan-Meier analysis and Cox proportional hazards regression model were performed to determine its prognostic significance. Results: Lipid profile including cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), LDL-C/HDL-C ratio, and ApoB/ApoA1 ratio were analyzed. For the first time, we found ApoB/ApoA1 ratio showed the biggest prognostic potency among all lipid-related variables and could act as an independent prognostic factor in GC. Patients with a high ApoB/ApoA1 ratio (≥1) had a shorter overall survival (hazard ratio: 1.373, 95% confidence interval: 1.123-1.68; P=0.002). Conclusion: Preoperative serum ApoB/ApoA1 ratio might be used as a novel prognostic indicator of GC.

15.
Medicine (Baltimore) ; 97(2): e9097, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29480823

RESUMO

The role of palliative surgery is controversial in advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitors (TKIs) therapy.We evaluated safety and clinical outcomes in a single institution series of advanced GIST patients from January 2002 to December 2008.One hundred and fifty-six patients had been recruited, including 87 patients underwent surgical resection and 69 patients kept on TKIs treatment. Four patients had major surgical complications. Median follow-up was 38.3 months, the overall survival (OS) and progression-free survival (PFS) of the patients in surgical group were longer than the nonsurgical group, PFS: 46.1 versus 33.8 months (P < .01), OS: 54.8 versus 40.4 months. In the subgroup analysis for the patients received surgery, the median PFS for patients with progression disease, stable disease, and partial response was 33.3, 51.5, and 83.0 months, respectively (P < .01). Median OS was 68.0 months in those with only liver or peritoneal metastases, and 45.3 months in those with both metastases. Median PFS of patients underwent R0/R1 resection was 73.6 months compared with 35.8 months in R2 resection patients (P < .01).Patients with advanced GISTs have prolonged OS after debulking procedures. Surgery for patients who have responsive disease after TKIs treatment should be considered.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/cirurgia , Cuidados Paliativos , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Proteínas Tirosina Quinases/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento
16.
Oncotarget ; 8(12): 19980-19996, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28212545

RESUMO

Small nucleolar RNAs (snoRNAs) have been implicated in the development of many cancers. We therefore examined the differential expression of snoRNAs between gallbladder cancer (GBC) tissues and matched adjacent non-tumor tissues using expression microarray analysis with confirmation by quantitative real-time PCR (qRT-PCR). Western blot analysis showed that SNORA74B levels were higher in GBC than non-tumor tissues. SNORA74B expression was positively associated with local invasion, advanced TNM stage, CA19-9 level, and Ki67 expression in patients with GBC, while it was negatively associated with expression of PHLPP, an endogenous Akt inhibitor. Moreover, SNORA74B expression was prognostic for overall survival (OS) and disease-free survival (DFS). Functional studies revealed that silencing SNORA74B in GBC cells using sh-SNORA74B suppressed cell proliferation, induced G1 arrest, and promoted apoptosis. Preliminary molecular investigation revealed that SNORA74B silencing inhibited activation of the AKT/mTOR signaling pathway, while increasing PHLPP expression. PHLPP depletion using shRNA abrogated sh-SNORA74B suppression of GBC cell proliferation, indicating that the antitumor effects of SNORA74B silencing were mediated by PHLPP. These findings define the important role of SNORA74B in cell proliferation, cell cycle, and apoptosis of GBC, and suggest that it may serve as a novel target for GBC treatment.


Assuntos
Neoplasias da Vesícula Biliar/prevenção & controle , Inativação Gênica , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Nucleolar Pequeno/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Proliferação de Células , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Fosfoproteínas Fosfatases/genética , Prognóstico , RNA Nucleolar Pequeno/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 7(48): 78640-78652, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27769047

RESUMO

Cytokine is a key molecular link between chronic inflammation and gallbladder cancer (GBC) progression. The potential mechanism of cytokine-associated modulation of microRNAs (miRNAs) expression in GBC progression is not fully understood. In this study, we investigated the biological effects and prognostic significance of interleukin-6 (IL-6) -induced miRNAs in the development of GBC. We identify that inflammatory cytokine, IL-6 promotes proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GBC both in vitro and in vivo. Among all the changed miRNAs in miRNA profiling, miR-33a expression was significantly decreased in IL-6 treated GBC cell lines, as well as in GBC tissues compared with case-matched normal tissues and cholecystitis tissues. In turn, miR-33a suppresses IL-6-induced tumor metastasis by directly binding Twist which was identified as an EMT marker. High expression of miR-33a suppressed xenograft tumor growth and dissemination in nude mice. The downregulation of miR-33a was closely associated with advanced clinical stage, lymph node metastasis, and poor clinical outcomes in patients with GBC. miR-33a acts as a tumor suppressor miRNA in GBC progression and may be considered for the development of potential therapeutics against GBC.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/metabolismo , Interleucina-6/farmacologia , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Proteínas Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Proteína 1 Relacionada a Twist/genética
18.
Cancer Res ; 76(18): 5361-71, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27450454

RESUMO

Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. ©2016 AACR.


Assuntos
Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Western Blotting , Proliferação de Células/fisiologia , Neoplasias da Vesícula Biliar/mortalidade , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Imunoprecipitação , Estimativa de Kaplan-Meier , Espectrometria de Massas , Análise de Sequência com Séries de Oligonucleotídeos , Piruvato Carboxilase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
19.
Cancer Lett ; 368(1): 88-96, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26254540

RESUMO

Sulfasalazine (SSZ) is an anti-inflammatory drug that has been demonstrated to induce apoptosis and tumor regression through inhibition of plasma membrane cystine transporter xc(-). Cysteine is a rate-limiting precursor for intracellular glutathione (GSH) synthesis, which is vital for compound detoxification and maintaining redox balance. Platinum-based chemotherapy is an important regimen used in clinics for various cancers including colorectal cancer (CRC). We hypothesized that targeting xc(-) transporter by SSZ may annihilate cellular detoxification through interruption of GSH synthesis and may enhance the anti-cancer activity of cisplatin (CDDP) by increasing drug transport. In the present study, we revealed that xCT, the active subunit of xc(-), is highly expressed in CRC cell lines and human colorectal carcinoma tissues compared with their normal counterparts. SSZ effectively depleted cellular GSH, leading to significant accumulation of reactive oxygen species and growth inhibition in CRC cells. In contrast, the normal epithelial cells of colon origin were less sensitive to SSZ, showing a moderate ROS elevation. Importantly, SSZ effectively enhanced the intracellular platinum level and cytotoxicity of CDDP in CRC cells. The synergistic effect of SSZ and CDDP was reversed by antioxidant N-acetyl-L-cysteine (NAC). Together, these results suggest that SSZ, a relatively non-toxic drug that targets cystine transporter, may, in combination with CDDP, have effective therapy for colorectal cancer.


Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/metabolismo , Sulfassalazina/farmacologia , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HT29 , Histonas/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
20.
Nutrients ; 7(6): 4689-704, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26066015

RESUMO

Advanced glycation end products (AGEs), the direct modulators of ß-cells, have been shown to cause insulin-producing ß-cell dysfunction and apoptosis through increase of intracellular reactive oxygen species (ROS) production. Sesamin has been demonstrated to possess antioxidative activity. This study was designed to investigate whether sesamin protects against AGEs-evoked ß-cell damage via its antioxidant property. The effects of sesamin were examined in C57BL/6J mice and MIN6 cell line. In in vivo studies, mice were intraperitoneally injected with AGEs (120 mg/kg) and orally treated with sesamin (160 mg/kg) for four weeks. Intraperitoneal glucose tolerance and insulin releasing tests were performed. Insulin content, ROS generation and ß-cell apoptosis in pancreatic islets were also measured. In in vitro studies, MIN6 cells were pretreated with sesamin (50 or 100 µM) and then exposed to AGEs (200 mg/L) for 24 h. Insulin secretion, ß-cell death, ROS production as well as expression and activity of NADPH oxidase were determined. Sesamin treatment obviously ameliorated AGE-induced ß-cell dysfunction and apoptosis both in vivo and in vitro. These effects were associated with decreased ROS production, down-regulated expression of p67(phox) and p22(phox), and reduced NADPH oxidase activity. These results suggest that sesamin protects ß-cells from damage caused by AGEs through suppressing NADPH oxidase-mediated oxidative stress.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Dioxóis/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Lignanas/farmacologia , Animais , Células Cultivadas , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
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