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1.
Anticancer Res ; 40(1): 75-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892554

RESUMO

BACKGROUND/AIM: The aim of the present study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. MATERIALS AND METHODS: We assessed HER2 expression using immunohistochemistry and/or fluorescence in situ hybridization in pre-treatment biopsied specimens and post-treatment resected specimens obtained from seven patients with advanced HER2-positive gastric cancer receiving trastuzumab-based chemotherapy. RESULTS: Four patients maintained the HER2-positive status and three patients had a change in HER2 expression from positive to negative. In patients showing the loss of HER2 expression after treatments, HER2-positive tumor cells with a dominant histological type disappeared, and HER2-negative tumor cells with another dominant histological type were identified. CONCLUSION: HER2 expression can change after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after treatments may be utilized to determine whether the continued use of trastuzumab is advisable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Imagem Multimodal/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Recidiva , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Trastuzumab/administração & dosagem , Resultado do Tratamento
2.
Anticancer Res ; 40(1): 81-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892555

RESUMO

BACKGROUND/AIM: Zinc finger protein ZKSCAN3 (ZNF306) is a promising oncogene candidate in colon, bladder, breast, uterine cervical, and prostate cancers. The present study aimed to investigate ZKSCAN3 protein expression in gastric carcinoma patient tissues and to evaluate oncological outcomes in these patients. MATERIALS AND METHODS: ZKSCAN3 was detected using the anti-ZKSCAN3 rabbit polyclonal antibody. For immunohistochemical examination, we used paraffin-embedded specimens from 87 consecutive patients with gastric cancer who underwent gastrectomy. We investigated ZKSCAN3 expression in relation with patient prognosis and clinicopathological factors. RESULTS: ZKSCAN3 was detected in 28 (32.2%) tumour specimens, with significant association with lymphatic system invasion and distant metastasis. Patients with ZKSCAN3-positive tumours had worse overall survival (OS) than those with ZKSCAN3-negative tumours based on log-rank testing. Furthermore, multivariate analysis revealed that ZKSCAN3 was an independent prognostic parameter for OS (hazard ratio: 2.6379, p=0.0164). CONCLUSION: ZKSCAN3 is a potential novel prognostic factor in gastric cancer patients.


Assuntos
Biomarcadores Tumorais , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Fatores de Risco , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo
3.
Life Sci ; 242: 117247, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899223

RESUMO

AIMS: Programmed death ligand 1 (PD-L1, CD274) has been reported to be expressed abnormally in many cancers, nevertheless, effect of PD-L1 on tumor cells remains unclear, especially in gastric cancer (GC). This study aimed to investigate the role of PD-L1 in metastasis and differentiation in GC. MAIN METHODS: Immunohistochemistry was performed on 237 paired GC tissues. shPD-L1 cells were generated by lentivirus shRNA solution and PD-L1-overexpressing cells were constructed by pcDNA3.1. Expression of PD-L1 and E-cadherin in GC cells were detected by western blot. KEY FINDINGS: PD-L1 expression was significantly lower in GC than that in adjacent normal tissues, especially in poorly differentiated and metastatic GC, but was positively correlated to survival time of patients. Moreover, PD-L1 ablation could decrease E-cadherin expression, promote cell migration and wound repair ability. In turn, overexpression of PD-L1 increased E-cadherin expression and inhibited wound repair ability. At the same time, All-trans retinoic acid (ATRA), which has the properties of pro-differentiation and inhibition of invasion and metastasis, upregulated the expression of PD-L1 and E-cadherin. SIGNIFICANCE: These findings not only identify PD-L1 may have a positive role for the treatment of GC, but also implicate that ATRA combined PD-L1 antibody drugs may enhance anti-tumor Immunity in GC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Gástricas/patologia , Antígeno B7-H1/fisiologia , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Gástricas/metabolismo
4.
J Photochem Photobiol B ; 202: 111698, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734436

RESUMO

Gastric cancer was a foremost one among the majority of regular carcinoma cases globally. Even the achievements on enhanced treatment approaches and early findings cannot decrease the mortality and morbidity ranges of gastric cancer. This current work was planned to develop Morus nigra-loaded zinc oxide nanoparticles (MN-ZnONPs) and to evaluate the different characteristic methods likes UV-vis spectroscopy, TEM, SEM, FT-IR, EDX and XRD. Furthermore, the anticancer effect of MN-ZnONPs against AGS cells were analysed via cell viability, apoptotic morphological variations by AO/EtBr, alterations of mitochondrial membrane potential (MMP), cell cycle arrest, lipid peroxidation status (TBARS), antioxidants (SOD, GSH and CAT) and generation of ROS. Moreover, the status of apoptosis gene such as Bax, caspase-9, caspase-3 and Bcl-2 expressions was analysed by using RT-PCR techniques. We observed the synthesized MN-ZnONPs have a spherical shape, crystalline nature and present different functional groups. We also observed that gastric cancer cells demonstrated in cell death by MN-ZnONPs treatments. The MN-ZnONPs induced apoptosis by enhanced formation of ROS, decreased MMP, apoptotic morphological modifications were evaluated by AO/EtBr, increased lipid peroxidation, decreased antioxidants and induced cell cycle arrest were observed. Furthermore, to confirm the molecular mechanism demonstrated of MN-ZnONPs to induce apoptosis by altering the gene expressions of apoptosis markers were observed.


Assuntos
Antineoplásicos/síntese química , Nanopartículas Metálicas/química , Morus/química , Óxido de Zinco/química , Antineoplásicos/farmacologia , Antioxidantes/química , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Química Verde , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Morus/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Gut ; 69(2): 231-242, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31068366

RESUMO

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes. DESIGN: We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. RESULTS: Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. CONCLUSIONS: Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.


Assuntos
Fator 4 Nuclear de Hepatócito/genética , Isocitrato Desidrogenase/metabolismo , Neoplasias Gástricas/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Marcação de Genes/métodos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Camundongos Endogâmicos NOD , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Gut ; 69(2): 243-251, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31085554

RESUMO

OBJECTIVE: Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. DESIGN: Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. RESULTS: CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal-epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. CONCLUSIONS: H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Gástricas/genética , Meios de Cultivo Condicionados , Metilação de DNA , DNA de Neoplasias/genética , Epigenômica/métodos , Ontologia Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Histona Desmetilases com o Domínio Jumonji/deficiência , Mutação , Nicho de Células-Tronco , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
7.
Life Sci ; 242: 117214, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884095

RESUMO

Accumulating evidence suggests that aberrant DNA methylation and gene silencing of tumor suppressors are pervasive in gastric malignancies, supporting reactivation of tumor suppressors through DNA demethylation as a potential therapeutic opportunity. Atp4a is an important tumor suppressor gene, encoding H+, K+-ATPase, and mediating gastric acid secretion in the stomach. Using transgenic gastric cancer model K19-Wnt1/C2mE (Gan) mice, by combining the transcriptome and MeDIP (methylated DNA immunoprecipitation) sequencing, together with qRT-PCR, we showed that Atp4a was expressed at low levels in tumor tissues and multiple GC cells, while both 5-aza-CdR and 18ß-glycyrrhetinic acid (GRA) pharmacological treatment triggered Atp4a activation with downregulation of DNMT1. In addition, CpG island (CGI) search showed that the CpG rich region is absent in the promoter region but present in exons 9-14 of Atp4a. Methylation specific PCR (MSP) indicated that Atp4a was fully or partly methylated in multiple GC cells. Further MassArray suggested that the demethylation in the CpG site 75, 183, 196, 262-268 might be responsible for the reactivation of Atp4a. Our research identified that GRA, a bioactive component found in abundance in Radix Glycyrrhiza, reactivated Atp4a expression and inhibited gastric tumorigenesis as a potential demethylation agent.


Assuntos
Metilação de DNA , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Inativação Gênica , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Humanos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Anticancer Res ; 39(12): 6645-6652, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810929

RESUMO

BACKGROUND/AIM: We have previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling was associated with the malignant progression of gastric cancer (GC). We thus examined the clinicopathological significance of CXCR2 ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, in GC. PATIENTS AND METHODS: The expression of CXCR2 ligands in 590 GC cases was investigated by immunohistochemistry. RESULTS: The expression was as follows: CXCL1, 46.2% (257/557); CXCL2, 20.7% (122/590); CXCL3, 17.1% (101/589); CXCL5/CXCL6, 2.9% (17/589); CXCL7, 36.4% (215/590); and CXCL8 1.7% (10/585) of the cases. High invasion depth was correlated with CXCL1 expression. Lymph node metastasis and peritoneal cytology positivity were correlated with high expression of CXCL1 and CXCL7. The prognoses of the CXCL1-positive patients were significantly poorer than those of the CXCL1-negative patients (p<0.001). CONCLUSION: Among the CXCR2 ligands, CXCL7 and especially CXCL1, might play an important role in the malignant progression of GC via CXCR2 signaling.


Assuntos
Proteínas de Neoplasias/metabolismo , Receptores de Interleucina-8B/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Análise de Variância , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocina CXCL5/metabolismo , Quimiocina CXCL6/metabolismo , Quimiocinas CXC/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-8/metabolismo , Ligantes , Metástase Linfática , Masculino , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , beta-Tromboglobulina/metabolismo
9.
Anticancer Res ; 39(12): 6711-6722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810936

RESUMO

BACKGROUND/AIM: Autophagy is a cellular mechanism that recycles cellular components to maintain homeostasis. To investigate the clinical implication of autophagy in gastric cancer, the autophagy markers with autophagosome formation, LC3B and selective autophagy substrate p62/SQSTM1 (P62) were validated. MATERIALS AND METHODS: LC3B and p62 expression was examined using immunohistochemistry, western blot assays, and reverse-transcription polymerase chain reaction (RT-PCR). The relationship of LC3B and p62 expression in gastric adenocarcinomas with clinicopathological parameters, including patient survival, were analyzed. RESULTS: Normal gastric mucosae exhibit no LC3B and p62 expression, while tubular adenoma and gastric adenocarcinomas exhibit variable nuclear or cytoplasmic p62 expression. High LC3B, high cytoplasmic p62, and low nuclear p62 protein expression in gastric adenocarcinomas is positively correlated with poor prognostic factors including survival. CONCLUSION: Dynamic LC3B and p62 changes are suggested to be involved in gastric tumorigenesis and cancer progression. LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for gastric adenocarcinomas.


Assuntos
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína Sequestossoma-1/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Adulto Jovem
10.
Anticancer Res ; 39(12): 6973-6979, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810969

RESUMO

BACKGROUND/AIM: Claudin18.2 (CLDN18.2) is a tight junction protein that has been identified as a promising target in gastric cancer. This study aimed to evaluate the clinical relevance of CLDN18.2 expression in gastric cancer. PATIENTS AND METHODS: This study included 367 patients diagnosed with gastric cancer, who underwent curative surgical resection. Immunohistochemical staining for CLDN18.2 was carried out, and expression was scored semi-quantitatively, based on staining intensity and the percentage of staining. RESULTS: CLDN18.2 expression was observed in 273 patients (74.4%), and 108 (29.4%) were classified as CLDN18.2-positive by predefined criteria. CLDN18.2 expression was not correlated with age, sex, tumor location, or stage. Expression rates were higher in diffuse-type and HER2-positive tumors. In multivariate survival analysis, CLDN18.2 expression was not associated with survival outcomes. CONCLUSION: Higher expression of CLDN18.2 was observed in diffuse-type and HER2-positive gastric cancers. Meanwhile, CLDN18.2 expression was not associated with survival in patients with gastric cancer.


Assuntos
Claudinas/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Isoformas de Proteínas/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Análise de Sobrevida
11.
Medicine (Baltimore) ; 98(52): e18449, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876727

RESUMO

Twist and E-cadherin are crucial for the development of different types of cancer; however, their clinical significance in adenocarcinoma of the gastroesophageal junction (AGE) remains unknown. Here, we investigated the correlation between the expression of Twist and E-cadherin and their impact on the clinical outcomes and prognosis of patients with AGE and proximal gastric carcinoma (PGC).Using immunohistochemistry, we determined the expression of Twist and E-cadherin in the tissue samples of patients with AGE and PGC. The correlation of the expression of Twist and E-cadherin with the clinicopathological factors was assessed by using the chi-square test, Fisher exact test, and non-parametric Mann-Whitney U test. The Kaplan-Meier method along with the log-rank test and Cox proportional-hazards model were used to evaluate the correlation of Twist and E-cadherin expression with the overall survival (OS) of patients.Overall, 94 patients with AGE (n = 45, 47.87%) or PGC (n = 49, 52.13%) who underwent primary tumor resection were included in this study. The median follow-up period was 40.5 months. We observed a significant difference in the smoking status (P < .001) and differentiation grade (P = .004) between patients with AGE and PGC. There was a significant association of a high Twist expression with T stage (only in PGC, P = .008), lymph node metastasis (AGE, P = .075; PGC, P = .051), and advanced pathological stages (AGE, P = .019; PGC, P = .006). A low E-cadherin expression showed similar results; however, it was not significantly associated with the advanced pathological stages of AGE (P = .372). A low E-cadherin expression was significantly associated with a low differentiation grade of AGE (P = .002). In addition, a significant inverse relationship was observed between Twist and E-cadherin expression. The Kaplan-Meier survival analysis and Cox regression analysis revealed that a high Twist expression and low E-cadherin expression were independent prognostic factors for short OS of patients with AGE or PGC.A high Twist expression or low E-cadherin expression was associated with unfavorable clinicopathological factors and independently predicted short OS of patients with AGE or PGC.


Assuntos
Adenocarcinoma/metabolismo , Caderinas/metabolismo , Carcinoma/metabolismo , Junção Esofagogástrica/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Adenocarcinoma/química , Adenocarcinoma/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Caderinas/análise , Carcinoma/química , Carcinoma/diagnóstico , Junção Esofagogástrica/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/química , Prognóstico , Neoplasias Gástricas/química , Neoplasias Gástricas/diagnóstico , Proteína 1 Relacionada a Twist/química
12.
Zhonghua Zhong Liu Za Zhi ; 41(11): 805-812, 2019 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-31770846

RESUMO

Objective: To clarify the effect of TRAF2 in the biological behavior of gastric cancer and explore the mechanism. Methods: TRAF2 stably depleted AGS cell was established. Cell growth was monitored by x-CELLigence system. Cell proliferation was detected using cell viability assay. The apoptosis and cell cycle were detected by flow cytometry. The difference of migration and invasion abilities were measured by real-time xCELLigence system and Transwell. The expression and activity of NF-κB signaling pathway were measured by western blot and TransAM assay. The expression of TRAF2 in gastric cancer tissue and its clinical significance were detected by immunohistochemistry. Results: The cell index of AGS-siTRAF2 cells was significantly lower than that of AGS-sictrl cells at 8 h. In the cell viability assay, the A values of AGS-siTRAF2 cells were 51 296.00±2 631.06, 68 389.25±6 703.21 and 65 559.50±6 339.22 at 24 h, 48 h and 72 h. The values of the viability of AGS-siTRAF2 cells were significantly lower than those of AGS-sictrl cells (P<0.001). The results of flow cytometry showed that the apoptosis rates of AGS-siTRAF2 cells were (1.42±0.07)%, (2.98±0.11)% and (1.56±0.03)% at 24 h, 48 h and 72 h, respectively, which were significantly higher than those of AGS-sictrl cells (all P<0.05). The distribution of S phase in AGS-siTRAF2 cells was (23.57±1.12)%, while that in the AGS-sictrl cells was (19.49±1.19)%. The difference was statistically significant (P=0.012). AGS-siTRAF2 cells migrated much slower than AGS-sictrl cells from 3 h and the number of migrated AGS-sictrl cells was 121.7±6.7 while that of AGS-siTRAF2 cells was 84.0±6.6 (P=0.002). The cell index of AGS-siTRAF2 cells was less than that of AGS-sictrl cells from 3 h. In Transwell assay, the number of invaded AGS-sictrl cells was 109.3±3.1 after 24 h of culture, significantly higher than 79.0±6.2 of AGS-siTRAF2 cells (P=0.002). Western blot analysis showed that the expression levels of RelA, RelB, p50 and p52 in AGS-siTRAF2 cells were significantly lower than those in AGS-sictrl cells. The activities of RelA, RelB, p50 and p52 in AGS-siTRAF2 cells were 0.01±0.00, 0.01±0.01, 0.92±0.01 and 0.53±0.03, respectively, significantly lower than those of AGS-sictrl cells (all P<0.001). High TRAF2 expression (TRAF2-high) was found in 53.0% of GC samples, while TRAF2-high was only observed in 38.0% of the paired adjacent tissues (P=0.033). The expression of TRAF2 was significantly higher in the tubular adenocarcinoma, poor differentiation advanced T, advanced N, and clinical staging (P<0.05). The median survival time were 17 months and 78 months in the TRAF2 high-expression and low-expression groups, respectively, and the difference was statistically significant (P=0.010). Conclusions: Depletion of TRAF2 inhibits the AGS cell growth, migration and invasion. The expression of TRAF2 is increased in gastric tumor tissue. The expression of TRAF2 is associated with the prognosis of gastric cancer.


Assuntos
Neoplasias Gástricas/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Invasividade Neoplásica , Transdução de Sinais
13.
Anticancer Res ; 39(11): 5903-5910, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704814

RESUMO

BACKGROUND: Gastric cancer (GC) exhibits heterogeneous clinical and molecular features, requiring the development of new biomarkers to further understand this disease. Our transcriptomic analysis detected overexpression of melanoma-associated antigen A6 (MAGEA6) in metastatic GC, leading us to determine the clinical significance of MAGEA6 in GC. MATERIALS AND METHODS: Fourteen GC cell lines and 230 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. Polymerase chain reaction array analysis was performed to identify coordinately expressed cancer-related genes, and immunohistochemistry (IHC) was used to detected MAGEA6 expression in situ. RESULTS: MAGEA6 mRNA levels were positively correlated with the expression of matrix metallopeptidase 9 mRNA. MAGEA6 mRNA levels were higher in GC tissues compared with those in normal adjacent tissues. Patients with high MAGEA6 expression had significantly worse prognosis. MAGEA6 protein levels in primary lesions predicted the likelihood of recurrence. CONCLUSION: Overexpression of MAGEA6 in GC tissues represents a promising biomarker for assessing the malignant phenotype of GC.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Gastrectomia/mortalidade , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/secundário , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Carcinoma de Células em Anel de Sinete/metabolismo , Carcinoma de Células em Anel de Sinete/secundário , Carcinoma de Células em Anel de Sinete/cirurgia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/secundário , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
14.
Anticancer Res ; 39(11): 6125-6133, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704840

RESUMO

AIM: The aim of the study was to identify novel biomarkers that are vital for improving management of patients with gastric cancer (GC). MATERIALS AND METHODS: An RNA-sequencing analysis was conducted using gastric tissue from patients with metastatic GC. In vitro cell functions were evaluated by siRNA-mediated knockdown assays. A total of 230 pairs of gastric tissue were subjected to expression analysis of mRNA and protein in situ. The serum levels of the candidate biomarker were determined by ELISA. RESULTS: MELTF was identified as a candidate biomarker. Inhibition of MELTF expression suppressed the invasion ability of GC cells. Increased tissue MELTF mRNA expression was associated with shorter survival. Furthermore, staining intensity of tissue MELTF protein was linked to recurrence rates. Serum MELTF levels gradually were increased from healthy controls to advanced GC. Patients with high serum MELTF levels had poor prognosis. CONCLUSION: Both tissue and serum MELTF levels may serve as biomarkers of GC progression.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Glicoproteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/sangue , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Células Tumorais Cultivadas
15.
Anticancer Res ; 39(11): 6155-6163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704843

RESUMO

BACKGROUND/AIM: Fluoxetine, an antidepressant, has cytotoxic effects on several cancer cell lines, while paclitaxel is an antineoplastic agent for various cancers. The aim of this study was to evaluate whether fluoxetine enhances the cytotoxic effect of paclitaxel in gastric adenocarcinoma cells and determine the mechanism of cell death. MATERIALS AND METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability and perform cell cycle analysis. Annexin V propidium iodide (PI) staining, 4',6-diamidino-2-phenylindole (DAPI) staining, caspase-3/7 assay, and western blot analysis were performed for determining cell death. RESULTS: Fluoxetine enhanced the anti-proliferative effect of paclitaxel. Fluoxetine-paclitaxel combination caused G2/M arrest and increased events in the sub G0/G1 phase in a time and dose-dependent manner, indicating apoptotic cell death. Combination treatment caused an increase in early apoptotic and late apoptotic cell death compared to single treatment alone. CONCLUSION: Fluoxetine enhanced the antiproliferation effect of paclitaxel in gastric adenocarcinoma AGS cells and the combination caused cell death by triggering apoptosis and necroptosis.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Fluoxetina/farmacologia , Necrose , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Captação de Serotonina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas
16.
Bull Cancer ; 106(11): 946-958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711572

RESUMO

AIM: A HER2-specific second-generation chimeric antigen receptor (5.137.z) was introduced into NK-92 cells, designated as NK-92/5.137.z cells. To evaluate the function and effectiveness of NK-92/5.137.z cells against gastric cancer cells and further determined whether combination with apatinib can synergize with this NK cell-based practice to better suppress gastric cancer. METHODS: The expression of HER2 was examined in gastric cancer. The in vitro and in vivo cytotoxic activities of NK-92/5.137.z cells with or without apatinib were evaluated against gastric cancer cell lines. RESULTS: HER2 proteins were over-expressed in a considerable proportion of gastric cancer cells. NK-92/5.137.z cells specifically lysed gastric cancer cells expressing HER2 and had higher levels of cytokine production. In vivo, NK-92/5.137.z cells were particularly efficient at eliminating small tumor xenografts, whereas larger solid tumors were not effectively controlled with NK-92/5.137.z cells. Treatment with apatinib increased NK cell infiltration into large tumor xenografts and improved the therapeutic efficacy of NK-92/5.137.z cells. CONCLUSION: NK-92/5.137.z cells could represent a novel treatment option for patients with gastric cancer, either used alone or combined with apatinib.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Piridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Neoplasias Gástricas/terapia , Animais , Antígeno CD56/metabolismo , Degranulação Celular , Linhagem Celular Tumoral , Terapia Combinada/métodos , Xenoenxertos , Humanos , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Lentivirus , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Medicine (Baltimore) ; 98(45): e17799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702632

RESUMO

Alpha-B crystallin (CRYAB), as a small heat shock protein, has been found to be highly expressed in various human cancers and significantly associated with the unfavorable prognosis of these tumor. Nevertheless, the clinical significance of CRYAB in gastric cancer (GC) angiogenesis remains to be elucidated. In this study, we evaluated the expression of CRYAB and CD34 in GC tissues and corresponding normal gastric specimens to explore whether high level CRYAB is related with the angiogenesis and the poor prognosis in GC.In this study, the expression of CRYAB and CD34 were detected in GC tissues and corresponding normal gastric tissues by immunohistochemical (IHC) technique. Furthermore, the relationship of CRYAB with CD34-evaluated microvessel density (MVD) and poor prognosis was also investigated.CRYAB expression level was significantly higher in GC tissue than in normal gastric mucosa tissue, and clearly mean higher MVD was observed in tumor tissues compared with non-cancerous tissues. Besides, higher MVD value was observed in positive CRYAB expression group than in negative CRYAB expression group. Statistical analysis showed that CRYAB and MVD are associated with clinicopathological features including lymph node metastasis (LNM), tumor differentiation, invasion depth, and TNM stages. Kaplan-Meier method and multivariate survival analysis indicated that high expression of CRYAB, MVD, invasion depth, TNM stages, and tumor differentiation, as well as LNM significantly correlate with poor prognosis of GC patients.High expression of CRYAB may contribute to angiogenesis, invasion and metastasis of GC. These results indicated that CRYAB was expected to be a promising molecular marker for poor prognosis and potential therapeutic target in patients with GC.


Assuntos
Antígenos CD34/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima , Cadeia B de alfa-Cristalina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/metabolismo , Análise de Sobrevida
18.
Int J Nanomedicine ; 14: 6575-6585, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616144

RESUMO

Background and purpose: In a past study, we developed and optimized a novel cationic PEGylated niosome containing anticancer drugs (doxorubicin or quercetin) and siRNA. This study intended to evaluate the anti-tumor effects of the combination therapy to target both the proteins and genes responsible for the development of gastric cancer. CDC20, known as an oncogene, is a good potential therapeutic candidate for gastric cancer. Methods: In order to increase the loading capacity of siRNA and achieve appropriate physical properties, we optimized the cationic PEGylated niosome in terms of the amount of the cationic lipids. Drugs (doxorubicin and quercetin) and CDC20siRNA were loaded into the co-delivery system, and physical characteristics, thermosensitive controlled-release, gene silencing efficiency, and apoptosis rate were determined. Results: The results showed that the designed co-delivery system for the drugs and gene silencer had an appropriate size and a high positive charge for loading siRNA, and also showed a thermosensitive drug release behavior, which successfully silenced the CDC20 expression when compared with the single delivery of siRNA or the drug. Moreover, the co-delivery of drugs and CDC20siRNA exhibited a highly inhibitory property for the cell growth of gastric cancer cells. Conclusion: It seems that the novel cationic PEGylated niosomes co-loaded with anticancer drug and CDC20siRNA has a promising application for the treatment of gastric cancer.


Assuntos
Proteínas Cdc20/metabolismo , Doxorrubicina/uso terapêutico , Polietilenoglicóis/química , Quercetina/uso terapêutico , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Cátions , Proteínas Cdc20/genética , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose , Ácidos Graxos Monoinsaturados/química , Inativação Gênica/efeitos dos fármacos , Humanos , Lipossomos , Tamanho da Partícula , Compostos de Amônio Quaternário/química , Quercetina/farmacologia , RNA Interferente Pequeno/genética , Eletricidade Estática , Temperatura Ambiente
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1052-1058, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640951

RESUMO

OBJECTIVE: To explore association of the expression levels of adenylate cyclase-associated protein 2 (CAP2) in gastric cancer tissues with the histopathology and long-term prognosis of the malignancy. METHODS: This study was conducted among a total of 105 patients with gastric cancer undergoing radical gastrectomy in our hospital between January, 2010 and October, 2013. Immunohistochemistry was used to quantitatively assess the expression of CAP2 in gastric cancer tissues and the adjacent tissues. Based on the median relative expression level of CAP2 of 3.5, the patients were divided into low CAP2 expression group (n=52) and high CAP2 expression group (n=53). The Cox regression model was used to analyze the effect of CAP2 expression on the 5-year survival rate of the patients, and ROC curve analysis was used to assess the predictive value of CAP2 expression for the patients' long-term survival. RESULTS: Immunohistochemical analysis showed that the expression levels of CAP2 (P < 0.01) and Ki67 (P < 0.01) were significantly higher in gastric cancer tissues than in the adjacent tissues, and the expression level of CAP2 was positively correlated with Ki67 (P < 0.01), peripheral blood CEA (P < 0.01) and CA19-9 (P < 0.01). The percentages of patients with CEA≥5 µg/L, CA19-9≥37 kU/L, pathological grade of G3-G4, T stage of 3-4, and N stage of 2-3 were significantly higher in patients with high CAP2 expression than in those with low CAP2 expression (P < 0.05). Kaplan- Meier survival analysis showed that the 5-year survival rate was significantly lower in patients with a high CAP2 expression (P < 0.01). A high expression level of CAP2, CEA≥5µg/L, CA19-9≥37 and pathological grades G3-G4 were all independent risk factors for shortened 5-year survival after radical gastrectomy (P < 0.01). With the relative expression level of 3.45 as the cut-off value, the sensitivity of CAP2 was 70.15% for predicting death 5 years after the surgery, with a specificity of 71.05% and an area under the curve of 0.779 (P < 0.01). CONCLUSIONS: CAP2 is highly expressed in gastric cancer tissues in close relation with the tumor progression. CAP2 is an independent risk factor for 5-year survival rate after radical gastrectomy for gastric cancer and can be of clinical value in prognostic evaluation of the patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Gástricas/patologia , Gastrectomia , Humanos , Imuno-Histoquímica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida
20.
DNA Cell Biol ; 38(12): 1460-1469, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31657619

RESUMO

Multiple factors, including genetic and epigenetic fluctuations, have been linked to gastric cancer formation and progression. Cytosine methylation (5mC) has been recognized as a critical epigenetic mark in the mammalian genome. The recent discovery of 5-hydroxymethylcytosine (5hmC), which is generated by ten-eleven translocation (TET) enzymes, provides new perspectives to understand DNA methylation-related plasticity. In this study, we show that gastric tumors display significant loss of 5hmC. Using matched distant normal, peripheral, and tumor primary tissues, we performed genome-wide profiling of 5hmC and identified differentially hydroxymethylated regions (DhMRs) specifically associated with gastric tumors. Gene ontology analyses indicated that DhMRs (both loss of 5hmC and gain of 5hmC) were enriched among the genes involved in specific pathways. Interestingly, the binding motif of hypoxia-inducible factor 1 (HIF1) is enriched among both peripheral and tumor DhMRs, while the Myc-binding motif is specifically enriched among only tumor DhMRs. Tumor progression analyses revealed a unique set of DhMRs that correlate with tumor progression. These data together suggest that alteration of 5hmC could potentially contribute to the tumorigenesis of gastric tumors.


Assuntos
5-Metilcitosina/análogos & derivados , Adenocarcinoma/patologia , Metilação de DNA , Epigênese Genética , Genoma Humano , Neoplasias Gástricas/patologia , 5-Metilcitosina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Estudos de Casos e Controles , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
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