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1.
Gene ; 806: 145922, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34454032

RESUMO

Gastric cancer (GC)-derived cell lines were generally used in basic cancer research and drug screening. However, it is always concerned about the difference between cultured cells and primary tumor by oncologists. To address this question, we compared differentially expressed genes (DEGs) in primary cancers, healthy tissues, and cell lines both in vitro and in silico. Seven reported genes with decreased expression in GCs by DNA methylation were analyzed in our cohort studies and experimentally validation. Selected datasets from TCGA (The Cancer Genome Atlas), CCLE (The Broad Institute Cancer Cell Line Encyclopedia), and GTEx (The Genotype-Tissue Expression project) were used to represent GCs, GC-derived cell lines, and healthy tissues respectively in the in silico analysis. Thirty gastric tissues together with six cell lines were used for validations. Unexpectedly, we experimentally found that reported cancer-related downregulated genes were only found in cancer cell lines but not in biopsies. The unchanged gene expressions in primary GCs were generally consistent with our cohort study, using information from cancerous (TCGA) and healthy tissues (GETx). Substantial differences were also found between DEGs of cancer tissues (TGCA)/ healthy tissues (GTEx) pair and cell lines (CCLE)/ healthy tissues (GTEx) pair, which confirmed the significant differences between primary cancer and cancer cell lines. Moreover, elevated expression of YWHAQ (14-3-3 δ) and THBS1 were observed in the GC biopsies, which might be potential biomarkers for GC diagnosis, considering the increased YWHAQ and THBS1 associated with poor survival rates in gastric cancer patients. In sum, it is suggested that cautions should be taken when using GC cell lines to study genes that show great differences between cell lines and tissues.


Assuntos
Proteínas 14-3-3/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Trombospondinas/genética , Proteínas 14-3-3/metabolismo , Idoso , Atlas como Assunto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Conjuntos de Dados como Assunto , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Cultura Primária de Células , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Trombospondinas/metabolismo , Células Tumorais Cultivadas
2.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4167-4174, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467729

RESUMO

This study aimed to explore the effects of galangin on energy metabolism and autophagy in gastric cancer MGC803 cells and the underlying mechanism. Cell counting kit-8(CCK-8) was used to detect the effects of galangin at different concentrations on via-bility of MGC803 cells after 48 h intervention. Western blot was carried out to measure the effects of galangin on expression of proteins related to autophagy, nuclear factor-κB(NF-κB) pathway and energy metabolism, followed by the determination of its effects on mRNA expression of energy metabolism-related proteins by Real-time quantitative PCR(qPCR). The impact of galangin on autophagy was explored using AutophagyGreen dye reagent, with autophagosomes and lysosomes observed under the transmission electron microscope(TEM). Nude mice transplanted with gastric cancer MGC803 cells via subcutaneous injection were randomly divided into the following three groups: control(0.5% sodium carboxymethyl cellulose, once a day), 5-fluorouracil(5-FU, 50 mg·kg~(-1), twice a week), and galangin(120 mg·kg~(-1), once a day) groups. The body weight and tumor volume were measured once every three days with a vernier caliper at the same time point by the same person. After 21-d treatment, the tumor tissue was isolated and weighed for the calculation of the tumor-suppressing rate. The comparison with the control group revealed that galangin inhibited the viability of MGC803 cells, up-regulated the protein expression of microtuble-associated protein 1 light chain 3 B(LC3 B) Ⅱ, inhibited the phosphorylation of NF-κB pathway-related proteins, and promoted the formation of autophagosomes in MGC803 cells. However, it did not obviously affect the expression of energy metabolism-related proteins. Furthermore, galangin at 120 mg·kg~(-1) significantly reduced the tumor weight and volume in mice, enhanced LC3 BⅡ protein expression, and inhibited the phosphorylation of NF-κB pathway-related proteins. All these have suggested that galangin inhibited the growth of gastric cancer MGC803 cells both in vivo and in vitro, possibly by inhibiting the NF-κB pathway and enhancing autophagy.


Assuntos
NF-kappa B , Neoplasias Gástricas , Animais , Autofagia , Flavonoides , Camundongos , Camundongos Nus , NF-kappa B/genética , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
3.
Zhonghua Yi Xue Za Zhi ; 101(34): 2649-2652, 2021 Sep 14.
Artigo em Chinês | MEDLINE | ID: mdl-34510869

RESUMO

Gastric cancer (GC) is one of the malignant tumors with both high morbidity and mortality in China. Immunotherapy is expected to improve its prognosis. Molecular classification of GC based on multiple levels of assessment such as genes and tumor immune microenvironment (TiME), which can precisely screen the population with potential benefit from immunotherapy. It is helpful to make the treatment decision-making, and to further improve the efficacy of immunotherapy.


Assuntos
Neoplasias Gástricas , China , Humanos , Imunoterapia , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Microambiente Tumoral
4.
Anticancer Res ; 41(9): 4185-4202, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475038

RESUMO

Gastric cancer is one of the leading types of cancer with an annual death toll of 700,000 worldwide. Despite the fact that several agents are approved for its treatment, high percentage of recurrence and intractability of metastatic disease remain a major problem. The identification of new targets and modalities for treatment are therefore of high priority. We have searched the literature for microRNAs down-regulated in gastric cancer with efficacy in gastric cancer-related murine xenograft models after reconstitution therapy. Among the identified miRs were 25 miRs targeting transcription factors, seven of them regulating cell-cycle and apotosis-related targets, and five of them regulating GTPase-related targets such as GAPs and GEFs. According to criteria such as prognostic impact, functional data, and tractability, miR-133 b/a (MCL1) and miR-518 (MDM2) are suggested as potentially valuable targets for further evaluation and possible treatment of gastric cancer.


Assuntos
Regulação para Baixo , MicroRNAs/genética , Neoplasias Gástricas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Terapia de Alvo Molecular , Neoplasias Gástricas/tratamento farmacológico
5.
World J Surg Oncol ; 19(1): 283, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537058

RESUMO

BACKGROUND: To study the clinical value of miR-135 and miR-20a combined with multi-detector computed tomography (MDCT) in the diagnosis of gastric cancer (GC). METHOD: A total of 146 patients with GC admitted to our hospital from January 2017 to June 2019 were selected and enrolled in the GC group. Another 103 patients with gastritis received in the same period were selected for the non-GC group. Besides, 95 healthy subjects who received physical examination in our hospital were selected into the healthy control group. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of serum miR-135 and miR-20a for each group. MDCT was used for detecting the clinical staging map of the enrolled patients. Pearson's correlation analysis was used to analyze the correlation between serum miR-135 and miR-20a in patients with GC. The receiver operating characteristic (ROC) curve was drawn to analyze value of miR-135 and miR-20a in the diagnosis of GC. RESULTS: Compared with non-GC group and healthy control group, the levels of serum miR-135 and miR-20a increased significantly in the GC group, while no significant difference was found between non-GC group and healthy control group (P > 0.05). Analysis of the relationship with clinical characteristics showed that the expression of serum miR-135 and miR-20a in the GC group was significantly correlated with the progression of GC, TNM stage, degrees of differentiation, status of lymph node metastasis, and distant metastasis (P < 0.01). Pearson's correlation analysis results showed positive correlations between miR-135 and miR-20a (r = 0.634, P = 0.000). The ROC analysis results showed that the optimal diagnostic values of miR-135 and miR-20a for GC were 7.56 and 5.82 respectively. The area under the curve (AUC) was 0.873 and 0.793 respectively. The 95% confidence interval (CI) was 0.811-0.935 and 0.697-0.890 respectively. The sensitivity and specificity of miR-135 and miR-20a combined with MDCT in the diagnosis of GC were 90.41% and 93.20% respectively. The sensitivity of combined use was significantly higher than that of single detection (P < 0.01). CONCLUSION: There are high expression levels of serum miR-135 and miR-20a in patients with GC. A combined detection of miR-135 and miR-20a with MDCT can improve the diagnostic sensitivity of GC and improve the accuracy of the final diagnosis. Therefore, multiple combined detection is valuable in the diagnosis of GC.


Assuntos
MicroRNAs , Neoplasias Gástricas , Biomarcadores Tumorais/genética , Humanos , MicroRNAs/genética , Tomografia Computadorizada Multidetectores , Prognóstico , Curva ROC , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/genética
6.
Georgian Med News ; (315): 165-168, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34365444

RESUMO

Gastric carcinoma represents one of the major causes of cancer related mortality worldwide. Recently, immunotherapeutic means gave the new promise for the treatment of gastric carcinoma, although, not all patients benefit from this type of treatment. Tumor infiltrating lymphocytes (TILs) are considered as one of the promising prognostic and predictive biomarkers in solid tumors. However, the presence of TILs is not well characterised in different types of gastric cancer. The aim of our study was to characterise TILs profile in different histopathological and molecular subtypes of gastric carcinomas. We used standard haematoxylin and eosin staining (H&E) for evaluation of TILs and immunohistochemistry to detect molecular markers, including CDH1, Ki67, p53 and Her2. The results of our study revealed that TILs status varies significantly in different histological and molecular subtypes of gastric adenocarcinoma, which might be the reason for different prognosis in these patients. Also, high TILs status is significantly related to the presence of p53 mutations in both enteric type and diffuse type gastric carcinomas, which can be further explored for immunotherapeutic options in these patients.


Assuntos
Adenocarcinoma , Neoplasias da Mama , Neoplasias Gástricas , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral , Prognóstico , Neoplasias Gástricas/genética
7.
World J Gastroenterol ; 27(28): 4653-4666, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366627

RESUMO

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5' and 3' untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.


Assuntos
Neoplasias Gástricas , Anti-Inflamatórios não Esteroides , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2 , Variações do Número de Cópias de DNA , Humanos , Inflamação , Isoenzimas , Proteínas de Membrana , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral
8.
Zhonghua Zhong Liu Za Zhi ; 43(8): 856-860, 2021 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-34407591

RESUMO

Objective: To evaluate the expression of semaphorin 5B (SEMA5B) in gastric adenocarcinoma and its relationship with prognosis. Methods: In November 2019, the clinicopathological characteristics and SEMA5B mRNA expression data of 341 patients with gastric adenocarcinoma were collected through TCGA database. The relationship between SEMA5B expression in gastric adenocarcinoma tissues and clinical pathologic features and overall survival were analyzed. Gene Set Enrichment Analysis (GSEA) was used to analyze the signaling pathways regulated by SEMA5B. Results: The expression level of SEMA5B mRNA in 341 gastric adenocarcinoma tissues was 0.577±0.587, in adjacent normal tissues was 0.132±0.075, the difference was statistically significant (P<0.001). The median survival time of 109 patients with high expression of SEMA5B mRNA was 14.5 months, 232 patients with low expression of SEMA5B mRNA was 17.9 months (P=0.047). Univariate analysis showed that the expression of SEMA5B mRNA was correlated with histological grade and T stage (P<0.05). The multivariate analysis revealed that age<65 years remained independently associated with overall survival, with a hazard ratio(HR) of 1.042 (95%CI: 1.021-1.064). The multivariate analysis revealed that high expression of SEMA5b mRNA remained independently associated with overall survival, with a HR of 1.195 (95%CI: 0.925-2.551). GSEA showed that malignant tumor signaling pathways (P=0.008), MAPK signaling pathways (P=0.047) and Notch signaling pathways (P=0.029) were differentially enriched in SEMA5B highly expressed phenotype. Conclusions: SEMA5B expression may be a potential prognostic molecular marker for prognosis of GAC patients. Moreover, malignant tumor signaling pathway, MAPK signaling pathway and Notch signaling pathway may be the key pathway regulated by SEMA5B in GAC.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Humanos , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
9.
World J Surg Oncol ; 19(1): 259, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461926

RESUMO

BACKGROUND: The aberrant expression of circular RNAs (circRNAs) plays vital roles in the advancement of human cancers, including gastric cancer (GC). In this study, the functions of circRNA ring finger protein 111 (circ-RNF111) in GC were investigated. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed for the levels of circ-RNF111, microRNA-876-3p (miR-876-3p) and krueppel-like factor 12 (KLF12) mRNA. RNase R assay was conducted for the feature of circ-RNF111. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, wound-healing assay, and transwell assay were applied for cell viability, colony formation, migration, and invasion, respectively. Flow cytometry analysis was used to analyze cell apoptosis and cell cycle process. The glycolysis level was examined using specific commercial kits. Western blot assay was carried out to measure the protein levels of hexokinase 2 (HK-2) and KLF12. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the combination between miR-876-3p and circ-RNF111 or KLF12. Murine xenograft model was constructed for the role of circ-RNF111 in vivo. Immunohistochemistry (IHC) was used for KLF12 level. RESULTS: Circ-RNF111 was higher expressed in GC tissues and cells than normal tissues and cells. Silencing of circ-RNF111 restrained cell viability, colony formation, migration, invasion, cell cycle process and glycolysis and induced apoptosis in GC cells in vitro. Circ-RNF111 positively regulated KLF12 expression via absorbing miR-876-3p. MiR-876-3p downregulation reversed the impacts of circ-RNF111 silencing on GC cell malignant phenotypes. MiR-876-3p overexpression repressed GC cell growth, metastasis and glycolysis, inhibited apoptosis and arrested cell cycle, while KLF12 elevation weakened the effects. Besides, circ-RNF111 knockdown inhibited tumor growth in vivo. CONCLUSION: Circ-RNF111 knockdown relieved the development of GC by regulating miR-876-3p/KLF12 axis.


Assuntos
Fatores de Transcrição Kruppel-Like , MicroRNAs , RNA Circular , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , MicroRNAs/genética , Proteínas Nucleares , Prognóstico , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases
10.
J Biomed Nanotechnol ; 17(7): 1305-1319, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34446134

RESUMO

Gastric adenocarcinoma (GAC) is one kind of gastric cancer with a high incidence rate and mortality. It is essential to study the etiology of GAC and provide theoretical guidance for the prevention and treatment of GAC. Bioinformatics was used via differential expression analysis, weighted gene co-expression network analysis, gene set enrichment analysis, and a training support vector machine (SVM) model to construct a TSIX/mir-320a/Rad51 network as the research index of GAC disease. On the basis of CRISPR/Cas9 gene editing technology, the present study utilizes the Cation lipid-assisted PEG-6-PLGA polymer nanoparticle (CLAN) drug carrier system to prepare the target knock-out TSIX drug with CRISPR/CaS9 nucleic acid. Knocking down lncRNA TSIX restored the suppression role of miR-320a on Rad51 and inhibited the Rad51 expression. Simultaneously, this ceRNA network activated the ATF6 signaling pathway after endoplasmic reticulum stress to promote GAC cells' apoptosis and inhibit the disease. TSIX/miR-320a/Rad51 network may be a potential biological target of GAC disease and provides a new strategy for treating GAC disease.


Assuntos
MicroRNAs , Nanopartículas , RNA Longo não Codificante , Neoplasias Gástricas , Apoptose , Cátions , Humanos , Lipídeos , MicroRNAs/genética , Polímeros , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Máquina de Vetores de Suporte
11.
In Vivo ; 35(5): 2771-2777, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410967

RESUMO

BACKGROUND/AIM: Cancer stem cells (CSCs) are reported to associated with cancer metastasis, relapse, and chemoresistance. This study examined the clinical significance of the expression of two CSC markers, the transporter associated with antigen processing 1 (TAP1) and the Delta-like 4 (DLL4) protein, in patients with locally advanced GC. PATIENTS AND METHODS: This study was performed using samples obtained from 413 pathological stage II/III GC patients after curative gastrectomy. We examined TAP1 and DLL4 expression using immunohistochemical analysis with tissue microarray and examined the association between TAP1 or DLL4 expression, clinicopathological factors and survival. RESULTS: High TAP1 expression was associated with better overall survival compared to low TAP1 expression (p=0.004). Furthermore, in multivariate analysis, high TAP1 expression was defined as a predictive factor for good survival. There was no significant difference between DLL4 expression and clinicopathological features and overall survival. CONCLUSION: TAP1 expression may be a useful prognostic marker in patients with locally advanced GC.


Assuntos
Neoplasias Gástricas , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Proteínas Adaptadoras de Transdução de Sinal , Apresentação do Antígeno , Proteínas de Ligação ao Cálcio , Gastrectomia , Humanos , Recidiva Local de Neoplasia , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia
12.
Biomed Res Int ; 2021: 5521058, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337018

RESUMO

Background: Gastric cancer (GC) is the most common type of cancer. It is highly malignant and is characterized by rapid and uncontrolled growth. The antitumour activity of Baicalin was studied in multiple cancers. However, its mechanism of action has not been fully elucidated. We provided a systematic understanding of the mechanism of action of baicalin against GC using a transcriptome analysis of RNA-seq. Methods: Human GC cells (SGC-7901) were exposed to 200 µg/ml baicalin for 24 h. RNA-seq with a transcriptome, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify the antitumour effects of baicalin on SGC-7901 cells in vitro. A protein-protein interaction (PPI) network of differentially expressed genes (DEGs) was constructed. A competitive endogenous RNA (ceRNA) network was constructed and further analysed after validation using qRT-PCR. Results: A total of 68 lncRNAs, 20 miRNAs, and 1648 mRNAs were differentially expressed in baicalin-treated SGC-7901 GC cells. Three lncRNAs, 6 miRNAs, and 7 mRNAs were included in the ceRNA regulatory network. GO analysis revealed that the main DEGs were involved in the biological processes of the cell cycle and cell death. KEGG pathway analysis further suggested that the p53 signalling pathway was involved in the baicalin-induced antitumour effect on SGC-7901 cells. Further confirmation using qPCR indicated that baicalin induced an antitumour effect on SGC-7901 cells, which is consistent with the results of the sequencing data. Conclusions: In summary, the mechanism of baicalin against GC involves multiple targets and signalling pathways. These results provide new insight into the antitumour mechanism of baicalin and help the development of new strategies to cure GC.


Assuntos
Flavonoides/uso terapêutico , Perfilação da Expressão Gênica , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mapas de Interação de Proteínas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
13.
Ann Clin Lab Sci ; 51(4): 494-502, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452887

RESUMO

OBJECTIVE: Gastric cancer is one of the most common gastrointestinal malignancies. miRNAs (microRNAs) have been reported to play a pivotal role in the tumorigenesis of gastric cancer. However, the role of miR-643 in gastric cancer is not fully understood. METHODS: The expression of miR-643 in gastric cancer cell lines was detected by qRT-PCR (quantitative reverse transcription PCR). Cell viability, apoptosis, migration, and invasion were assessed using the Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound scratch and Transwell assays, respectively. The target gene of miR-643 was predicted by bioinformatics analysis and validated using luciferase reporter assay. RESULTS: The expression level of miR-643 in gastric cancer cell lines was lower than in the normal gastric epithelium cell line (GES-1). Overexpression of miR-643 inhibited cell viability and colony formation but promoted cell apoptosis in gastric cancer. Transwell invasion assay and in vitro scratch assay evidenced that miR-643 overexpression inhibited gastric cancer cell migration and invasion. Bioinformatics analysis revealed that miR-643 could directly target TXNDC9 (Thioredoxin domain containing 9), and luciferase reporter assay validated this result. Further analysis showed that miR-643 mimics caused a significant reduction of TXNDC9 in gastric cancer cells. Moreover, TXNDC9 overexpression reversed the effects of miR-643 mimics on gastric cancer cell viability, invasion, and migration. CONCLUSION: miR-643 functions as a potential tumor suppressor in gastric cancer by inhibiting cell viability, colony formation, migration, and invasion via targeting TXNDC9, which provides a novel target for the diagnostic treatment of gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/patologia , Tiorredoxinas/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal , Humanos , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tiorredoxinas/genética , Células Tumorais Cultivadas
14.
Medicine (Baltimore) ; 100(33): e26850, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414935

RESUMO

BACKGROUND: Gastric cancer (GC) is a strong cause of global cancer mortality. Nucleotide excision repair (NER) can modulate platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. Some studies have found a link between excision repair cross complementation group 1 (ERCC1) rs2298881, one gene in NER pathway, and response to chemotherapy. However, the results have been disputed. METHODS: We conducted a meta-analysis to reevaluate the association between polymorphisms of NER gene (ERCC1 rs2298881) and the clinical outcomes in gastric cancer patients receiving platinum-based chemotherapy. Searching PubMed, Web of Science, EMBASE, Google Scholar, and China National Knowledge Infrastructure, 2 independent searchers found all pertinent literatures up to May 1, 2021. We enrolled studies according to consistent selection criteria, extracted and vitrified data. Crude odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were applied to evaluate the effect of ERCC1 rs2298881 on patients treated by platinum-based chemotherapy. RESULTS: By the data gathered from 6 independent studies, 1940 cases diagnosed with gastric cancer and treated with chemotherapy were included, containing 1208 Good-Responders and 732 Poor-Responders. With a comprehensive meta-analysis, we found that the patients with ERCC1 rs2298881A allele had a worse response to chemotherapy than those who with rs2298881C allele under allelic model (A vs C), with the pooled OR of 0.780 (95% CI: 0.611-0.996, P = .046). And our analysis indicated that AA genotype was associated with unfavorable overall survival (HR = 1.540, 95% CI = 1.106-2.144, P = .011) compared with CC genotype. CONCLUSIONS: ERCC1 rs2298881 is suggested as a marker of clinical outcome in gastric cancer patients treated by platinum-based chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Neoplasias Gástricas/mortalidade
15.
Medicine (Baltimore) ; 100(32): e26545, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397871

RESUMO

BACKGROUND: Plenty of studies have showed matrix metalloproteinase 14 (MMP14) expression might be associated with the prognosis of gastric cancer (GC). However, no definite conclusion has been obtained for the contradictory results. METHODS: We searched PubMed, Web of science, Embase, and Cochrane library for eligible studies. The association between MMP14 expression and prognostic outcomes of GC was evaluated. Hazard ratio (HR) and 95% confidence interval (CI) were integrated to show the effect of MMP14 expression on the overall survival (OS) or recurrence-free survival (RFS). Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was used to validate the association of MMP14 expression with OS or RFS in GC. A brief bioinformatics analysis was also performed to determine the prognostic role of MMP14 expression in GC. RESULTS: High MMP14 expression was associated with shorter OS compared to low MMP14 expression in GC (HR = 1.95, P < .01). Patients with high MMP14 expression tended to have worse differentiation (P = .03), deeper tumor invasion (P < .01), earlier lymph node metastasis (P < .01), earlier distant metastasis (P < .01) and more advanced clinical stage (P < .01) compared to those with low MMP14 expression. The data from TCGA and GEO showed MMP14 was overexpressed in tumor tissues compared to normal tissues (P < .05), and high MMP14 expression was significantly related to shorter OS (HR = 1.70, 95% CI = 1.32-2.20, P < .01) and RFS (HR = 1.45, 95% CI = 1.15-1.83, P < .01) compared to low MMP14 expression in GC. Expression of MMP14 was linked to functional networks involving the biological process, metabolic process, response to stimulus, cell communication and so on. Functional network analysis suggested that MMP14 regulated the protein digestion and absorption, extracellular matrix receptor interaction, focal adhesion, ribosome, spliceosome, and so on. CONCLUSION: High MMP14 expression was associated with worse prognosis of GC compared to low MMP14 expression. MMP14 expression could serve as a prognostic factor and potential therapeutic target of GC.


Assuntos
DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 14 da Matriz/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Progressão da Doença , Humanos , Metaloproteinase 14 da Matriz/biossíntese , Prognóstico , Neoplasias Gástricas/metabolismo
16.
J Transl Med ; 19(1): 339, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372878

RESUMO

BACKGROUND: DNA damage response plays critical roles in tumor pathogenesis and radiotherapy resistance. Protein phosphorylation is a critical mechanism in regulation of DNA damage response; however, the key mediators for radiosensitivity in gastric cancer still needs further exploration. METHODS: A quick label-free phosphoproteomics using high-resolution mass spectrometry and an open search approach was applied to paired tumor and adjacent tissues from five patients with gastric cancer. The dysregulated phosphoproteins were identified and their associated-pathways analyzed using Gene Set Enrichment Analysis (GSEA). The mostly regulated phosphoproteins and their potential functions were validated by the specific antibodies against the phosphorylation sites. Specific protein phosphorylation was further analyzed by functional and clinical approaches. RESULTS: 832 gastric cancer-associated unique phosphorylated sites were identified, among which 25 were up- and 52 down-regulated. Markedly, the dysregulated phosphoproteins were primarily enriched in DNA-damage-response-associated pathways. Particularly, the phosphorylation of Bcl-2-associated transcription factor 1 (BCLAF1) at Ser290 was significantly upregulated in tumor. The upregulation of BCLAF1 Ser290 phosphorylation (pBCLAF1 (Ser290)) in tumor was confirmed by tissue microarray studies and further indicated in association with poor prognosis of gastric cancer patients. Eliminating the phosphorylation of BCLAF1 at Ser290 suppressed gastric cancer (GC) cell proliferation. Upregulation of pBCLAF1 (Ser290) was found in association with irradiation-induced γ-H2AX expression in the nucleus, leading to an increased DNA damage repair response, and a marked inhibition of irradiation-induced cancer cell apoptosis. CONCLUSIONS: The phosphorylation of BCLAF1 at Ser290 is involved in the regulation of DNA damage response, indicating an important target for the resistance of radiotherapy.


Assuntos
Neoplasias Gástricas , Apoptose , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , Humanos , Fosforilação , Tolerância a Radiação , Neoplasias Gástricas/genética , Neoplasias Gástricas/radioterapia
17.
J Transl Med ; 19(1): 342, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372882

RESUMO

BACKGROUND: We tried to elaborate the molecular mechanism of ETS-like transcription factor 4 (ELK4) affecting gastric cancer (GC) progression through M2 polarization of macrophages mediated by lysine-specific demethylase 5A (KDM5A)-Praja2 (PJA2)-kinase suppressor of ras 1 (KSR1) axis. METHODS: GC expression dataset was obtained from GEO database, and the downstream regulatory mechanism of ELK4 was predicted. Tumor-associated macrophages (TAMs) were isolated from GC tissues. The interaction among ELK4, KDM5A, PJA2 and KSR1 was analyzed by dual luciferase reporter gene, ChIP and Co-IP assays. The stability of KSR1 protein was detected by cycloheximide (CHX) treatment. After TAMs were co-cultured with HGC-27 cells, HGC-27 cell biological processes were assessed through gain- and loss-of function assays. Tumorigenicity was detected by tumorigenicity test in nude mice. RESULTS: In GC and TAMs, ELK4, KDM5A and KSR1 were highly expressed, while PJA2 was lowly expressed. M2 polarization of macrophages promoted the development of GC. ELK4 activated KDM5A by transcription and promoted macrophage M2 polarization. KDM5A inhibited the expression of PJA2 by removing H3K4me3 of PJA2 promoter, which promoted M2 polarization of macrophages. PJA2 reduced KSR1 by ubiquitination. ELK4 promoted the proliferative, migrative and invasive potentials of GC cells as well as the growth of GC xenografts by regulating KSR1. CONCLUSION: ELK4 may reduce the PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A to promote M2 polarization of macrophages, thus promoting the development of GC.


Assuntos
Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Humanos , Ativação de Macrófagos , Macrófagos , Camundongos , Camundongos Nus , Proteína 2 de Ligação ao Retinoblastoma , Neoplasias Gástricas/genética , Ativação Transcricional , Ubiquitina-Proteína Ligases , Proteínas Elk-4 do Domínio ets
18.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383427

RESUMO

BACKGROUND: Gastric cancer (GC) remains the fourth-leading malignancy worldwide and has a high mortality rate. Accumulating evidence reveals that long noncoding RNAs (lncRNAs) play essential roles in tumorigenesis and metastasis and can be used as potential biomarkers for diagnosis and prognosis. METHODS: We downloaded gene expression profiles from the National Center of Biotechnology Information Gene Expression Omnibus (GEO), screened lncRNAs differentially expressed in gastric cancer tissues and adjacent tissues, and then constructed a lncRNA-miRNA-mRNA network. Seventy patients with gastric cancer were divided into two groups according to different clinical characteristics. The expression of lncRNA LUCAT1 in gastric cancer was detected by reverse transcription polymerase chain reaction (RT-PCR). The AGS and SGC-7901 cell lines were used in CCK8 assay, apoptosis, cell cycle test, transwell assay, and wound healing assay. RESULTS: The expression level of LUCAT1 was associated with tumor diameter (p < 0.001), tissue differentiation grade (p = 0.026), and LNM status (p = 0.020) in GC. The results showed that the lncRNA LUCAT1 could promote the proliferation, invasion, and migration of GC cells, inhibit the apoptosis of GC cells, and affect the process of cell cycles. CONCLUSIONS: The lncRNA LUCAT1 may be used as a potential biomarker for early signs of LNM in GC and may play a crucial role in the development of GC.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética
19.
J Transl Med ; 19(1): 325, 2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332586

RESUMO

BACKGROUND: General role of cancer-associated fibroblast (CAF) and its infiltration characteristics in gastric cancer remains to be unknown. METHODS: We estimate CAF infiltration in bulk tumor tissue with RNA-seq data and analyzed its relationship with gastric cancer subtype, survival and immune microenvironment. RESULTS: We revealed CAF intend to have higher infiltration in diffuse, genomically stable, and advanced gastric cancer. CAF is associated with immunosuppressive microenvironment. Wide transcriptomics alterations occur in high CAF infiltrated gastric cancer, PI3K/AKT, TGFB and Hedgehog pathway are remarkable in this procedure. We utilized receptor tyrosine kinases and TGFB pathway ligands to construct risk score system that can predict survival. CONCLUSION: Thus, CAF is associated with aggressive phenotype of gastric cancer and risk score based on RTK and TGFB pathway ligands expression is a promising tool for assessment of gastric cancer survival.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Gástricas , Proteínas Hedgehog , Humanos , Imunossupressão , Fosfatidilinositol 3-Quinases , Neoplasias Gástricas/genética , Microambiente Tumoral
20.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
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