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1.
Medicine (Baltimore) ; 99(5): e18864, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000390

RESUMO

Nuclear factor-κB-inducing kinase (NIK) is a new regulator of nuclear factor-κB signaling, which plays an important role in tumorigenesis. This study aimed to examine the expression of NIK in gastric cancer and investigate its clinical significance.Tumor issues were collected from 80 gastric cancer patients who received surgery and the diagnosis was confirmed by postoperative pathological analysis. The expression of NIK in gastric cancer tissues and adjacent normal mucosa was detected by immunohistochemical analysis. The associations between NIK expression and clinicopathological features of the patients were further analyzed.NIK expression was significantly higher in gastric cancer tissues than in adjacent normal tissues (P < .05). Furthermore, NIK expression showed significant association with UICC stage, T status, and differentiation, but not with age and gender of gastric cancer patients.NIK is overexpressed in gastric cancer and is a potential diagnostic marker of gastric cancer.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Gástricas/enzimologia , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
2.
Anticancer Res ; 40(2): 695-702, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014910

RESUMO

BACKGROUND/AIM: Few studies have examined the genetic role of matrix metalloproteinases (MMPs) to early detection or prediction in gastric cancer development. In this study, the contribution of MMP7 promoter (A-181G and C-153T) polymorphic genotypes to gastric cancer risk in Taiwanese was investigated for the first time. MATERIALS AND METHODS: A total of 121 cases and 363 controls were enrolled and their MMP7 genotypes at A-181G and C-153T were examined by polymerase chain reaction-restriction fragment length polymorphism methodology using genomic DNA from serum. RESULTS: The GG genotype at MMP7 A-181G was found to represent a risk factor for gastric cancer, especially among smokers. No individual with variant genotype carrier at MMP7 C-153T was found among this Taiwanese population. CONCLUSION: The G allele of MMP7 A-181G may serve as an early predictor for gastric cancer risk in Taiwanese; other gastric cancer markers are still urgently needed.


Assuntos
Metaloproteinase 7 da Matriz/genética , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Taiwan
3.
J Cancer Res Clin Oncol ; 146(2): 329-342, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912229

RESUMO

PURPOSE: Members of the aaRS (aminoacyl-tRNA synthetase) family are proteins controlling the aminoacylation process, in which YARS (tyrosyl-tRNA synthetase) catalyzes the binding of tyrosine to its cognate tRNA and plays an important role in basic biosynthesis. Several studies have demonstrated the association between YARS mutation and certain developmental abnormalities/diseases, yet YARS's linkage with cancer remains uncategorized. In this study, by combining in silico, in vitro, and in vivo studies, we explored the expressions and functions of YARS in gastric cancer (GC). METHODS: We evaluated YARS's distribution in tumor and paired normal tissues/specimens of GC by referring to large cohort online datasets and patient-derived tissue specimens. YARS-related changes were assessed by phenotypical/molecular experiments and RNA-sequencing analysis in GC cell lines harboring YARS knockdown or overexpression. RESULTS: Both the transcript and protein levels of YARS were evidently higher in gastric cancer tissues than in paired normal tissues. YARS knockdown induced repressed proliferation and invasiveness, as well as enhanced apoptosis in GC cell lines, while abnormally upregulating YARS expression promoted gastric cancer growth in vivo. We inferred based on RNA-sequencing that YARS modulates multiple cancerous signaling pathways and proved through cellular experiments that YARS promoted GC progression, as well as homologous recombination by activating PI3K-Akt signaling. CONCLUSIONS: By revealing the existence of a YARS-PI3K-Akt signaling axis in gastric cancer, we discovered that tRNA synthetase YARS is a novel tumorigenic factor, characterized by its upregulation in tumor-derived specimens, as well as its functions in promoting gastric cancer progression.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/enzimologia , Tirosina-tRNA Ligase/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Tirosina-tRNA Ligase/biossíntese , Tirosina-tRNA Ligase/genética , Regulação para Cima
4.
Anticancer Res ; 40(1): 341-347, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892585

RESUMO

BACKGROUND/AIM: The prognostic significance of biomarkers related to gastric cancer prognosis has not been fully elucidated. The aim of study was to use immunohistochemical biomarkers to reveal prognosis. PATIENTS AND METHODS: A total of 682 patients who had undergone curative surgery were evaluated regarding the correlation of prognosis and immunohistochemical biomarkers. RESULTS: The COX2-positive groups showed a poor 5-year overall and disease-free survival. Further analysis revealed that COX2 positivity was a significant risk factor for poorer disease-free survival in the group with clinical stage I disease (p=0.016). We also noted a marked trend between COX2 positivity and poorer overall survival. The COX2-positive group showed general postoperative pathological up-staging compared with the COX2-negative group. CONCLUSION: This study showed the potential of COX2 as a biomarker for gastric cancer prognosis. Preoperative evaluation of COX2 might be a useful tool for generating optimal treatment strategies in patients with clinical stage I gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida
5.
J Cancer Res Clin Oncol ; 146(1): 287-295, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667572

RESUMO

PURPOSE: Trastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the optimal maintenance treatment in patients benefited from the first line therapy remains unclear. METHODS: In this prospective observational study, patients with HER2 positive AGC who received six cycles of trastuzumab-based first line chemotherapy were divided into two arms according to the maintenance strategy: trastuzumab monotherapy (arm A) and trastuzumab plus mono-chemo-agent derived from the initial chemotherapy (arm B). The primary end point was overall survival (OS), the secondary end points were first line progression free survival (PFS), maintenance PFS, cost-effectiveness ratios (CERs), incremental cost-effectiveness ratios (ICERs) and safety. RESULTS: 30 patients were in arm A received trastuzumab monotherapy and 48 were in arm B. The clinical and pathological characteristics of two arms were well balanced. There was no significant difference of median OS (16.5 vs 20.0 months, HR 0.71 P = 0.169) or PFS (7.9 vs 11.0, HR 1.06, P = 0.892) between two arms, however, adding chemo-agent could lead to a 29% reduction in mortality risk. Adverse effects including cardiac safety were also similar. Subgroup analysis showed chemotherapy additional to trastuzumab benefited on OS in patients who had stable disease (SD) of response (HR: 0.084, P = 0.004), elder than 65 years old (HR: 0.4, P = 0.015), without liver metastasis (HR: 0.271, P = 0.008) or less than two organs of distance metastasis (HR: 0.263, P = 0.005). The average cost per patients in arm A was 153,137 RMB and 165,195 RMB in arm B. While, ICER in arm A was 1.29 times higher than arm B (CERs of two arms were 19,384 vs 15,018 RMB). CONCLUSION: Mono-chemo-agent combined with trastuzumab showed an advantage of absolute value and hazard ratio on OS, in addition to ICER of PFS for patients who benefit from the initial six cycles of trastuzumab-based first line therapy, especially in patients with certain clinical or treatment-related characterisitics. A large sample randomized trial is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trastuzumab/administração & dosagem , Adulto Jovem
6.
J Cancer Res Clin Oncol ; 146(1): 75-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31754833

RESUMO

PURPOSE: The enzymes gamma-glutamyl hydrolase (GGH) and folylpolyglutamate synthetase (FPGS) regulate intracellular folate concentrations needed for cell proliferation, DNA synthesis, and repair. High GGH expression affects 5-FU thymidylate synthase (TS) inhibition and is a risk factor for various malignancies. Here, the clinical significance of GGH and FPGS expression was investigated in Stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1. METHODS: Surgical specimens of cancer tissue and adjacent normal mucosa, obtained from 253 patients with previously untreated gastric cancer, were examined. GGH and FPGS mRNA expression was measured by qPCR to evaluate their clinicopathological significance in gastric cancer patients after curative resection. RESULTS: While FPGS expression showed no significant differences between the cancerous and normal samples, GGH expression was higher in cancer tissue than in adjacent normal mucosa. High GGH expression was correlated with age, histological type, and vascular invasion. Overall survival (OS) of patients with high GGH mRNA expression was significantly poorer than of patients with low GGH expression. Multivariate analysis showed that high GGH expression was an independent prognostic factor of OS (HR: 2.58, 95% CI 1.29-5.16). Patients who received S-1 adjuvant treatment showed a significantly poor OS between high GGH/low FPGS and low GGH/high FPGS. Patients without adjuvant treatment showed no significant difference. CONCLUSION: GGH expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa. High GGH and low FPGS expression is a useful independent predictor of poor outcomes in stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/biossíntese , Peptídeo Sintases/biossíntese , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , gama-Glutamil Hidrolase/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Quimioterapia Adjuvante , Combinação de Medicamentos , Feminino , Mucosa Gástrica/enzimologia , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Peptídeo Sintases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem , gama-Glutamil Hidrolase/genética
7.
Med Sci Monit ; 25: 7770-7783, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31619663

RESUMO

BACKGROUND Our previous research revealed that membrane type 1-matrix metalloproteinase (MT1-MMP) is overexpressed and plays a crucial role in gastric cancer (GC) progression. Exosomes are important for GC carcinogenesis, and the exosomal contents are ideal biomarkers. However, the expression of exosomal MT1-MMP mRNA in serum and its potential significance in GC remains unclear. MATERIAL AND METHODS The expression of exosomal MT1-MMP mRNA in serum of patients with GC, chronic gastritis, or atypical hyperplasia, and healthy controls was detected using real-time quantitative RT-PCR. Serum CEA, CA19-9, and CA72-4 were also measured by electrochemiluminescence assay. RESULTS Exosomes were isolated and identified in serum, and serum exosomal MT1-MMP mRNA was found to be higher in patients with GC compared with healthy controls and patients with chronic gastritis or atypical hyperplasia (all P<0.05). Serum exosomal MT1-MMP mRNA was significantly correlated with tumor diameter, differentiation, Borrmann type, invasion depth, lymphatic metastasis, distal metastasis, and TNM stage. The AUC of exosomal MT1-MMP mRNA was 0.788 (95% CI: 0.714-0.850) with 63.9% sensitivity and 87.1% specificity, and was higher than that of CEA (0.655 (95% CI: 0.573-0.730)). The combination of 2 markers gave an AUC of 0.821 (95% CI: 0.750-0.878), which was better than with the individual marker. The sensitivity, specificity, and positive and negative predictive values were 75.6%, 83.9%, 94.7%, and 47.3%, respectively. Moreover, the multiple logistic regression model showed that tumor diameter, differentiation, invasion depth, and exosomal MT1-MMP mRNA were the risk factors for lymphatic metastasis in GC. CONCLUSIONS Our results characterized serum exosomal MT1-MMP mRNA in GC, providing a foundation for discovering serum exosomes-targeted biomarkers for GC diagnosis.


Assuntos
Exossomos/genética , Metaloproteinase 14 da Matriz/genética , RNA Mensageiro/sangue , Neoplasias Gástricas/enzimologia , Adulto , Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Progressão da Doença , Exossomos/metabolismo , Feminino , Humanos , Metástase Linfática , Masculino , Metaloproteinase 14 da Matriz/sangue , Pessoa de Meia-Idade , RNA Mensageiro/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética
8.
Int J Mol Sci ; 20(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480591

RESUMO

The MET tyrosine receptor kinase is essential for embryonic development and tissue regeneration by promoting cell survival, proliferation, migration, and angiogenesis. It also contributes to tumor development and progression through diverse mechanisms. Using human cancer cell lines, including Hs746T (MET-mutated/amplified), H596 (MET-mutated), and H1993 (MET-amplified) cells, as well as BEAS-2B bronchial epithelial cells, we investigated whether MET is involved in the regulation of immune checkpoint pathways. In a microarray analysis, MET suppression using a MET inhibitor or siRNAs up-regulated co-stimulatory molecules, including 4-1BBL, OX40L, and CD70, and down-regulated co-inhibitory molecules, especially PD-L1, as validated by measuring total/surface protein levels in Hs746T and H1993 cells. MET activation by HGF consistently increased PD-L1 expression in H596 and BEAS-2B cells. Co-culture of human peripheral blood mononuclear cells with Hs746T cells suppressed interferon-γ production by the immune cells, which was restored by MET inhibition or PD-L1 blockade. A significant positive correlation between MET and PD-L1 expression in lung cancer was determined in an analysis based on The Cancer Genome Atlas (TCGA) and in an immunohistochemistry study. The former also showed an association of MET overexpression in a PD-L1high tumor with the decreased expressions of T-cell effector molecules. In summary, our results point to a role for MET overexpression/activation in the immune escape of tumors by PD-L1 up-regulation. MET-targeted-therapy combined with immunotherapy may therefore be an effective treatment strategy in patients with MET-dependent cancer.


Assuntos
Carcinoma/enzimologia , Leucócitos Mononucleares/imunologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Antígeno B7-H1/metabolismo , Carcinoma/imunologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Humanos , Interferon gama/metabolismo , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/metabolismo
9.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489901

RESUMO

Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism of action is poorly understood. Here, we explored acid sphingomyelinase as a possible new target of gentamicin in cancer. Since gastric cancer is one of the most common cancers and represents the second cause of death in the world, we performed the study in NCI-N87 gastric cancer cell line. The effect of the drug resulted in the inhibition of cell proliferation, including a reduction of cell number and viability, in the decrease of MIB-1 proliferative index as well as in the upregulation of cyclin-dependent kinase inhibitor 1A and 1B (CDKN1A and CDKN1B), and growth arrest and DNA-damage 45A (GADD45A) genes. The cytotoxicity was apoptotic as shown by FACS analysis. Additionally, gentamicin reduced HER2 protein, indicating a minor tumor aggressiveness. To further define the involvement of sphingomyelin metabolism in the response to the drug, gene and protein expression of acid and neutral sphingomeylinase was analyzed in comparison with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and vitamin D receptor (VDR), molecules involved in cancer. Gentamicin induced a downregulation of PTEN, VDR, and neutral sphingomyelinase and a strong upregulation of acid sphingomyelinase. Of note, we identified the same upregulation of acid sphingomyelinase upon gentamicin treatment in other cancer cells and not in normal cells. These findings provide new insights into acid sphingomyelinase as therapeutic target, reinforcing studies on the potential role of gentamicin in anticancer therapy.


Assuntos
Inibidores Enzimáticos/farmacologia , Gentamicinas/farmacologia , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Neoplasias Gástricas/enzimologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
10.
Nutrients ; 11(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491956

RESUMO

Reactive oxygen species (ROS) contribute to the oncogenic phenotype of cancer cells by acting as signaling molecules for inducing proliferation. ROS are known to activate the epidermal growth factor receptor (EGFR), which causes the activation of the Ras/mitogen-activated protein kinases (MAPKs) pathway. The Ras-dependent pathway promotes the activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB), a transcriptional modulator of cyclooxygenase-2 (COX-2) that induces cell proliferation. Lycopene is a potent antioxidant carotenoid and is responsible for the red color of fruits and vegetables. This study aims to investigate whether lycopene inhibits proliferation and induces apoptosis in gastric cancer AGS cells by suppressing the EGFR/Ras/MAPK and NF-κB-COX-2 signaling axis. Lycopene decreased cell viability and increased apoptotic indices (DNA fragmentation, apoptosis inducing factor, cleavage of caspase-3 and caspase-9, Bax/Bcl-2 ratio). Lycopene reduced the level of intracellular and mitochondrial ROS and decreased the activation of the ROS-mediated EGFR/Ras/extracellular signal-regulated kinase (ERK) and p38 MAPK pathways, thus leading to attenuation of the DNA-binding activity of NF-κB p50/p50 and the level of COX-2 gene expression. These results show that lycopene-induced apoptosis and inhibition of proliferation occur via inhibition of ROS-activated EGFR/Ras/ERK and p38 MAPK pathways and NF-κB-mediated COX-2 gene expression in AGS cells. In conclusion, consumption of lycopene-enriched foods could decrease the incidence of gastric cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Ciclo-Oxigenase 2/metabolismo , Licopeno/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Proteínas ras/metabolismo
11.
Gene ; 716: 144034, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377317

RESUMO

BACKGROUND: Outcome in adjuvant chemotherapy of gastric cancer (GC) has considerable stage-independent variability, which underscores the need for prognostic or predictive molecular markers. CHAF1A promotes tumor growth while its impact on chemotherapy outcome remains unknown. METHODS: CHAF1A protein expression was measured in independent discovery and validation sets that included 86 and 325 patients respectively who received fluoropyrimidines-based adjuvant chemotherapy after radical gastrectomy. The chemosensitizing effect of CHAF1A knockdown was investigated in vitro. Bioinformatics analysis based on RNA-seq and proteome data from public database was performed to investigate the potential mechanisms and further validation was conducted. RESULTS: In both the discovery and validation sets, CHAF1A expression level was an independent predictor for disease-free survival (HR = 4.25; 95% CI: 2.31-7.79; P < 0.001; and HR = 1.91; 95% CI: 1.03-3.54; P = 0.039, respectively) and overall survival (HR = 3.25; 95% CI: 1.75-6.05; P < 0.001; and HR = 2.42; 95% CI: 1.12-5.20; P = 0.024, respectively) in patients with non-cardia GC but not in those with cardia GC. In GC cells, CHAF1A knockdown significantly decreased the IC50 of 5-FU. Bioinformatics analyses indicated that CHAF1A correlated with folate metabolism and the expression of thymidylate synthetase (TS). Furthermore, CHAF1A knockdown significantly reduced TS expression in GC cells and CHAF1A positively correlated with TS protein expression in tumor tissues. Finally, ten proteins potentially relevant to the regulation of TS expression by CHAF1A were identified using online tools based on RNA-seq and proteome data. CONCLUSIONS: CHAF1A may impact adjuvant chemotherapy outcome of GC by regulating the expression of TS.


Assuntos
Antineoplásicos/uso terapêutico , Chaperonas de Histonas/metabolismo , Pirimidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timidilato Sintase/metabolismo , Idoso , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Fator 1 de Modelagem da Cromatina/metabolismo , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Ácido Fólico/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Timidilato Sintase/genética , Resultado do Tratamento
12.
Oncol Rep ; 42(4): 1283-1294, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364750

RESUMO

Carboxypeptidase X, M14 family member 2 (CPXM2), has been associated with several human disorders such as developmental diseases. However, whether CPXM2 is involved in oncogenesis or tumor progression remains unclear. In the present study, we used clinical samples from gastric cancer (GC) patients to investigate potential roles of CPXM2 in GC. We also analyzed datasets from the Oncomine database, The Cancer Genome Atlas (TCGA), and the Kaplan­Meier Plotter to validate these results. We found that CPXM2 was overexpressed in GC and that the overexpression was associated with an unfavorable prognosis, regardless of the Lauren classification and tumor node metastasis staging. In addition, knockdown of CPXM2 in cultured GC cells significantly impeded cell proliferation and migration, as indicated by the cholecystokinin octapeptide, colony formation assay, scratch wound healing assay, and Transwell® migration assay. Furthermore, gene set enrichment analysis using RNA­seq data from TCGA indicated that high CPXM2 expression in GC patients was positively correlated with the HALLMARK_APICAL_JUNCTION and HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION gene sets. Finally, western blotting results revealed that several key molecules involved in the epithelial mesenchymal transition were regulated by CPXM2. Taken together, these results imply an active role for CPXM2 in promoting tumor aggressiveness via epithelial to mesenchymal transition (EMT) modulation in GCs.


Assuntos
Carboxipeptidases/biossíntese , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Idoso , Carboxipeptidases/genética , Carboxipeptidases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Regulação para Cima
13.
Biomed Pharmacother ; 117: 109165, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261030

RESUMO

Gastric cancer (GC) is one of the most lethal malignancies. Chemoresistance and metastasis are the main cause of treatment failure. Cancer stem cells (CSCs) have been proven to be essential for cancer metastasis and chemoresistance. PKCδ (protein kinase C-δ), a novel member of PKC family, has been validated as a synthetic lethal target in multiple cancers, and contributes to tyrosine kinase inhibitors (TKI) resistance in EGFR-mutant NSCLC (non-small cell lung cancer) patients. However, its role in GC is unclear. Here, we systematically investigate its role in GC, especially in regulating GC stem cell-like properties. We found that PKCδ positively regulated the metastasis, chemoresistance, and stem cell-like characteristics of GC cells, and its inhibitor sotrastaurin could rescue the above effects mediated by PKCδ. Importantly, sotrastaurin could also weaken metastasis, chemoresistance, and stem cell-like characteristics of adriamycin-resistant GC cells via PKCδ suppression, indicating sotrastaurin is an ideal candidate for combinational therapy to overcome chemoresistance for GC.


Assuntos
Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Proteína Quinase C-delta/metabolismo , Pirróis/farmacologia , Quinazolinas/farmacologia , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos
14.
Asia Pac J Clin Oncol ; 15(5): e191-e196, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309731

RESUMO

AIM: Nicotinamide Nucleotide Transhydrogenase (NNT) gene encodes a protein, which is an important antioxidative enzyme that converts NADH to NADPH. This enzyme provides a significant proportion of the entire NADPH resource in the mitochondria. Previous reports have shown possible contribution of this gene in the carcinogenesis process. METHODS: In the current research, we evaluated expression levels of NNT gene and a naturally occurring antisense RNA (NNT-AS1) in gastric cancer specimens compared to their corresponding adjacent noncancerous tissues (ANCTs). RESULTS: Both NNT1 and NNT-AS1 genes were significantly downregulated in tumor tissues compared to ANCTs (expression ratio = 0.369, p = .045 and expression ratio = 0.368, p = .043, respectively). Transcript levels of NNT1 and NNT-AS1 were associated with the location of the primary tumor (p = .003 and .002, respectively). Moreover, expressions of both genes were significantly elevated in tumors with lymphatic/vascular invasion compared to tumors without lymphatic/vascular invasion (p = .001 and p = .005). No other remarkable associations were noticed between transcript levels of genes in tumor tissues and patients' information. Based on the area under curve (AUC) values in the receiver operating characteristic (ROC) curves, the diagnostic power of NNT1 and NNT-AS1 were estimated to be 0.62 and 0.63, respectively. CONCLUSIONS: Although we demonstrated dysregulation of NNT1 and NNT-AS1 in gastric tumor specimens in association with clinical data of patients, these two genes are not supposed to be appropriate biomarkers for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/metabolismo , RNA Antissenso/metabolismo , Neoplasias Gástricas/patologia , Adolescente , Adulto , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/genética , Prognóstico , RNA Antissenso/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Adulto Jovem
15.
Genes Chromosomes Cancer ; 58(11): 798-803, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31124195

RESUMO

Up to 85% of gastrointestinal stromal tumors (GIST) harbor mutually exclusive mutations in the KIT or the PDGFRA gene. Among others, known as wild type GIST, succinate dehydrogenase (SDH)-deficient tumors develop due to genetic or epigenetic alterations in any of four SDH genes. Herein, we present a unique case of SDH-deficient GIST with an unusual heterogeneous SDHA and SDHB staining pattern and mutations detected in the SDHA and KIT gene. A 50-year-old patient presented with a 5 cm large gastric tumor with a multinodular/plexiform growth pattern, mixed epithelioid and spindle cell morphology, and focal pronounced nuclear atypia with hyperchromasia and high mitotic activity. Immunohistochemically, CD117 and DOG-1 were positive. SDHB and SDHA stains showed loss of expression in some of the nodules, whereas others presented with an unusually weak patchy positivity. Molecular analysis revealed a point mutation in exon 5 of the SDHA gene and a mutation in exon 11 of the KIT gene. We hypothesize that based on the allele frequency of SDHA and KIT mutations the tumor is best regarded as SDH-deficient GIST in which the SDHA mutation represents the most likely driver mutation. The identified KIT mutation raises the distinct possibility that the KIT mutation is a secondary event reflecting clonal evolution. This is the first case of a treatment naïve GIST harboring a somatic SDHA and a KIT mutation, challenging the dogma that oncogenic mutations in treatment naïve GIST are mutually exclusive.


Assuntos
Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Succinato Desidrogenase/deficiência , Feminino , Tumores do Estroma Gastrointestinal/metabolismo , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Mutação , Oncogenes , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
16.
Acta Oncol ; 58(9): 1205-1211, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31109224

RESUMO

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzyme defect worldwide. There is a growing scientific evidence for a protective role of G6PD deficiency against carcinogenesis. In this retrospective analysis, we tested the hypothesis that G6PD deficiency may reduce the risk of developing cancer in a tissue-specific manner. Material and methods: The study was conducted using data from 11,708 subjects undergoing gastrointestinal endoscopic procedures between 2002 and 2018 and tested for G6PD status in a teaching hospital of Northern Sardinia, Italy. Results: A 40% reduction of risk for cancer of endodermal origin was observed among G6PD-deficient patients compared with subjects with normal enzyme activity (relative risk (RR) 0.61, 95% confidence interval (CI) 0.47-0.80) in both genders, confirmed by multivariable generalized linear regression after adjusting for age, sex, smoking habits, body mass index, diabetes and socio-economic status. The 'protective' effect of G6PD deficiency was larger for gastric cancer (RR 0.41, 95% CI 0.18-0.99), hepatocellular carcinoma (RR 0.48, 95% CI 0.26-0.92) and colorectal cancer (RR 0.72, 95% CI 0.53-0.98), while a non-significant risk was observed for breast, prostate, lung, hematopoietic and metastases (primary site unknown). Conclusions: Our results suggest a reduced susceptibility to develop cancers, mostly of endodermal origin (stomach, colon and liver), but not of ectodermal/mesodermal origin, in carriers of G6PD deficiency. The effects of G6PD deficiency on carcinogenesis need further studies to better understand how cancer cells originating from different germ layers use pentose phosphate pathway to proliferate.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase/sangue , Neoplasias/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/enzimologia , Neoplasias da Mama/enzimologia , Carcinoma Hepatocelular/enzimologia , Estudos de Casos e Controles , Neoplasias Colorretais/enzimologia , Intervalos de Confiança , Suscetibilidade a Doenças , Feminino , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Humanos , Modelos Lineares , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Neoplasias da Próstata/enzimologia , Estudos Retrospectivos , Neoplasias Gástricas/enzimologia
17.
J Biol Chem ; 294(20): 8238-8258, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30940726

RESUMO

The subcellular mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastric cancer and normal mucosal cells is elusive because of the diverse cyclooxygenase-independent effects of these drugs. Using human gastric carcinoma cells (AGSs) and a rat gastric injury model, here we report that the NSAID indomethacin activates the protein kinase Cζ (PKCζ)-p38 MAPK (p38)-dynamin-related protein 1 (DRP1) pathway and thereby disrupts the physiological balance of mitochondrial dynamics by promoting mitochondrial hyper-fission and dysfunction leading to apoptosis. Notably, DRP1 knockdown or SB203580-induced p38 inhibition reduced indomethacin-induced damage to AGSs. Indomethacin impaired mitochondrial dynamics by promoting fissogenic activation and mitochondrial recruitment of DRP1 and down-regulating fusogenic optic atrophy 1 (OPA1) and mitofusins in rat gastric mucosa. Consistent with OPA1 maintaining cristae architecture, its down-regulation resulted in EM-detectable cristae deformity. Deregulated mitochondrial dynamics resulting in defective mitochondria were evident from enhanced Parkin expression and mitochondrial proteome ubiquitination. Indomethacin ultimately induced mitochondrial metabolic and bioenergetic crises in the rat stomach, indicated by compromised fatty acid oxidation, reduced complex I- associated electron transport chain activity, and ATP depletion. Interestingly, Mdivi-1, a fission-preventing mito-protective drug, reversed indomethacin-induced DRP1 phosphorylation on Ser-616, mitochondrial proteome ubiquitination, and mitochondrial metabolic crisis. Mdivi-1 also prevented indomethacin-induced mitochondrial macromolecular damage, caspase activation, mucosal inflammation, and gastric mucosal injury. Our results identify mitochondrial hyper-fission as a critical and common subcellular event triggered by indomethacin that promotes apoptosis in both gastric cancer and normal mucosal cells, thereby contributing to mucosal injury.


Assuntos
Apoptose/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Mucosa Gástrica/enzimologia , Indometacina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/enzimologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína Quinase C/metabolismo , Neoplasias Gástricas/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/genética , Linhagem Celular Tumoral , GTP Fosfo-Hidrolases/genética , Mucosa Gástrica/patologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/genética , Dinâmica Mitocondrial/genética , Proteínas Mitocondriais/genética , Proteínas de Neoplasias/genética , Proteína Quinase C/genética , Ratos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
18.
PLoS One ; 14(4): e0214872, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30934021

RESUMO

BACKGROUND: There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer. METHODS: Quantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010. RESULTS: (1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability. CONCLUSIONS: Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.


Assuntos
Biomarcadores Tumorais/genética , Cisteína Dioxigenase/genética , Neoplasias Gástricas/genética , Idoso , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Transfecção
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 215-221, 2019 02 28.
Artigo em Chinês | MEDLINE | ID: mdl-30890511

RESUMO

OBJECTIVE: To investigate the differentially expressed genes between gastric cancer and normal gastric mucosa by bioinformatics analysis, identify the important gene participating in the occurrence and progression of gastric cancer, and predict the functions of these genes. METHODS: The gene expression microarray data GSE100935 (including 18 gastric cancer samples and normal gastric mucosal tissues) downloaded from the GEO expression profile database were analyzed using Morpheus to obtain the differentially expressed genes in gastric cancer, and a cluster analysis heat map was constructed. The online database UALCAN was used to obtain the expression levels of these differentially expressed genes in gastric cancer and normal gastric mucosa. The prognostic value of the differentially expressed genes in gastric cancer was evaluated with Kaplan-Meier survival analysis. GO functional enrichment analysis was performed using Fun-Rich software, and the STRING database was exploited to establish a PPI network for the differentially expressed genes. RESULTS: A total of 45119 differentially expressed genes were identified from GSE100935 microarray data. Analysis with UALCAN showed an obvious high expression of EXD3 gene in gastric cancer, and survival analysis suggested that a high expression level of EXD3 was associated with a poorer prognosis of the patients with gastric cancer. GO functional enrichment analysis found that the differentially expressed genes in gastric cancer were involved mainly in the regulation of nucleotide metabolism and the activity of transcription factors in the cancer cells. CONCLUSIONS: EXD3 may be a potential oncogene in gastric cancer possibly in relation to DNA damage repair. The up-regulation of EXD3 plays an important role in the development and prognosis of gastric cancer, and may serve as an important indicator for prognostic evaluation of the patients.


Assuntos
Biologia Computacional , Exonucleases/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Bases de Dados Genéticas , Mucosa Gástrica/química , Mucosa Gástrica/enzimologia , Perfilação da Expressão Gênica , Humanos , Prognóstico , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade
20.
Med Sci Monit ; 25: 2032-2042, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30886134

RESUMO

BACKGROUND This systematic review of the literature and meta-analysis aimed to review the evaluation and monitoring of superoxide dismutase (SOD) activity and its clinical significance in gastric cancer. MATERIAL AND METHODS Systematic review involved searching the PubMed, Embase, Ovid, and the China National Knowledge Infrastructure (CNKI) databases. Search terms included 'superoxide dismutase,' and 'gastric cancer.' Studies that included measurements of SOD activity in peripheral blood samples in patients with SOD activity compared with healthy controls. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS Ten controlled clinical studies were identified that included six studies that measured SOD in serum, three in erythrocytes, and one study that measured SOD on whole blood. Meta-analysis, using the standardized mean difference (SMD) and the 95% confidence interval (CI), showed that patients with gastric cancer had significantly decreased SOD activity when compared with the healthy controls (SMD, -0.840; 95% CI, -1.463 to -0.218; p=0.008). Subgroup analysis was conducted on SOD distribution in the blood (erythrocyte: SMD, -1.773; 95% CI, -2.504 to -1.042; p=0.000) (serum SMD, -0.322; 95% CI, -1.006-0.361; p=0.355) (whole blood: SMD, -1.251; 95% CI, -1.731 to -0.771; p=0.000) and for male subjects (SMD, -2.090; 95% CI, -2.725 to -1.456; p<0.001). CONCLUSIONS Meta-analysis showed that SOD measurements from blood samples, especially in erythrocytes, had potential as a diagnostic and monitoring parameter in patients with gastric cancer.


Assuntos
Neoplasias Gástricas/enzimologia , Superóxido Dismutase/metabolismo , Biomarcadores Tumorais/sangue , Feminino , Humanos , Masculino , Neoplasias Gástricas/sangue , Superóxido Dismutase/sangue , Superóxido Dismutase-1/sangue , Superóxido Dismutase-1/metabolismo
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