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1.
Anticancer Res ; 41(4): 1831-1840, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813388

RESUMO

BACKGROUND/AIM: Peroxiredoxin V (Prx V) plays crucial roles in cellular apoptosis and proliferation in various cancer cells by regulating the cellular reactive oxygen species (ROS) levels. MATERIALS AND METHODS: Here, we examined the possible regulatory effects of Prx V on doxorubicin (DOX)-induced cellular apoptosis and its mechanisms in the human gastric adenocarcinoma cell line (AGS cells). RESULTS: Our findings suggest that Prx V knockdown may significantly increase the DOX-induced apoptosis by aggravating intracellular ROS accumulation. We also found that DOX-induced mitochondrial ROS levels and membrane permeability were significantly higher in short hairpin Prx V cells than in mock cells, and these phenomena were dramatically reversed by ROS scavenger treatment. Prx V knockdown also significantly upregulated the cleaved caspase 9, 3, and B-cell lymphoma 2 (Bcl2)-associated agonist of cell death/Bcl2 protein expression levels, suggesting that Prx V knockdown activates mitochondria-dependent apoptotic signaling pathways. CONCLUSION: Taken together, this study suggests that Prx V may be a strong molecular target for gastric cancer (GC) chemotherapy, and further elucidates the role of Prx V in oxidative stress-induced cell apoptosis.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Inativação Gênica , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Peroxirredoxinas/genética , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
2.
Biomed Pharmacother ; 133: 111075, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378974

RESUMO

N6-methyladenosine (m6A) is one of the most abundant messenger RNAs modification. Increasing evidence illustrates its critical role on gastric cancer. Here, present research focuses on the potential function of m6A methyltransferase Wilms' tumour 1-associated protein (WTAP) in gastric cancer tumorigenesis. Firstly, m6A immunoprecipitation sequencing analysis (MeRIP-Seq) analysis demonstrated the m6A profile in gastric cancer cells. Both WTAP and the m6A expression were up-regulated in gastric cancer tissue and cells. The high-expression of WTAP was closely correlated with poor prognosis of gastric cancer patients. Functional experiments illustrated that WTAP promoted the proliferation and glycolytic capacity (glucose uptake, lactate production and extracellular acidification rate) in vitro, and the knockdown of WTAP suppressed the tumor growth in vivo. Mechanistically, HK2 was identified to be the target of WTAP using MeRIP-Seq and MeRIP-qPCR. WTAP enhanced the stability of HK2 mRNA through binding with the 3'-UTR m6A site. In conclusion, our results demonstrate the oncogenic role of WTAP and its m6A-mediated regulation on gastric cancer Warburg effect, providing a novel approach and therapeutic target in gastric cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Hexoquinase/metabolismo , Fatores de Processamento de RNA/metabolismo , Neoplasias Gástricas/enzimologia , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Estabilidade Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fatores de Processamento de RNA/genética , Estabilidade de RNA , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Carga Tumoral
3.
Gene ; 754: 144859, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32535049

RESUMO

DNA topoisomerases essentially remove topological strains generated during DNA replication, transcription, DNA repair, and other cytogenetic processes. However, distinct expression level and prognostic significance of individual topoisomerase isoforms in gastric cancer (GC) remain largely unexplored. In this study, we utilized Oncomine and Kaplan-Meier plotter database to detect the mRNA expression level of individual topoisomerase isoforms as well as assess their prognostic significance in GC patients. With the exception of TOP3B and TOP2B, levels of all topoisomerase isoforms were found to be elevated in GC patients when compared to the normal tissues. Elevated expression of TOP1 and TOP1MT was relevant to longer overall survival (OS) in GC and gastric intestinal type adenocarcinoma (GITA) patients, but not in diffuse gastric adenocarcinoma (DFA) patients. Increased expression of TOP2A and TOP2B was related to better OS in GC, as well as in GITA and DFA patients. In contrast, increased expression TOP3A and TOP3B was associated with shorter OS in GC, as well as in GITA and DFA patients. We also applied the Tumor IMmune Estimation Resource (TIMER) tool to assess the correlations between distinct topoisomerase isoforms and the infiltrating immune cell landscape. Furthermore, we found that down-regulating the expression of TOP3A by shRNA significantly inhibited the proliferation and colony formation in GC cells compared to control shRNA treated cells. Thus our study lays the framework for utilizing topoisomerases in better understanding the complexity and heterogeneity of GC and for developing strategies for novel customized therapy in GC patients.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Neoplasias Gástricas/patologia , Adenocarcinoma/enzimologia , Biomarcadores Tumorais/genética , DNA Topoisomerases Tipo II/genética , Precursores Enzimáticos , Perfilação da Expressão Gênica , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Neoplasias Gástricas/enzimologia , Taxa de Sobrevida
4.
Adv Exp Med Biol ; 1221: 351-363, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274717

RESUMO

Heparanase is upregulated in various tumors, and its expression is closely associated with tumor growth, angiogenesis and metastasis, which accomplishes this mainly through degrading heparan sulfate and releasing heparin-binding growth factors thereby influencing multiple signaling pathways. In addition to its enzymatic degrading activity, heparanase can act via its non-enzymatic mechanisms that directly regulate various signaling. This review mainly focuses on the expression levels and role of heparanase in gastric cancer, and multiple genes and mechanisms regulating heparanase expression in gastric cancer. Furthermore, the development of heparanase-targeted immunotherapy and its potential application for treating gastric cancer are discussed.


Assuntos
Glucuronidase/metabolismo , Imunoterapia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Progressão da Doença , Glucuronidase/genética , Humanos , Metástase Neoplásica , Neovascularização Patológica , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética
5.
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
6.
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
7.
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
8.
Cancer Biother Radiopharm ; 35(3): 199-207, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31976763

RESUMO

Background: This study aims at investigating the effect of the Weifufang, an effective prescription for the treatment of gastric cancer developed by the Traditional Chinese Medicine (TCM)/Combination of TCM and Western Medicine Department of the Hunan Cancer Hospital, on gastric cancer xenografts in nude mice and its effect on the PTEN gene; it also aims at exploring the possible tumor suppression mechanism. Methods: Nude mice with xenografts were treated with different concentrations of the Weifufang for 2 weeks, and changes in tumor volume were observed. The histopathology of the tumor was detected by hematoxylin and eosin staining; PTEN gene expression in tumor tissues was detected by immunohistochemistry (IHC) and western blot. Results: After 2 weeks of treatment, tumor inhibition rates in the 5-flourouracil (5-FU) group, and in the Weifufang low-, middle-, and high-dose groups were 30.67%, 19%, 49.52%, and 29.36%, respectively. The IOD of the PTEN gene was detected by IHC. The values in the water group, the 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.013 ± 0.004, 0.085 ± 0.062, 0.041 ± 0.024, 0.128 ± 0.032, and 0.061 ± 0.052, respectively. Except for the 5-FU group, the differences between the gastric compound middle dose-group and the other groups were statistically significant (p < 0.05). Results of PTEN expression detection by western blot: The expression levels in the water group, 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.2240 ± 0.0172, 0.4200 ± 0.0228, 0.2760 ± 0.0163, 0.3840 ± 0.0133, and 0.3040 ± 0.0211, respectively. Except for the 5-FU group, differences between the Weifufang middle-dose group and the other groups were statistically significant (p < 0.05). Conclusion: The Weifufang may inhibit the growth of gastric cancer xenografts by upregulating PTEN gene expression. The middle-dose group had the best effect.


Assuntos
Adenocarcinoma/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , PTEN Fosfo-Hidrolase/biossíntese , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , PTEN Fosfo-Hidrolase/genética , Distribuição Aleatória , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Am J Clin Nutr ; 111(3): 570-579, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31968072

RESUMO

BACKGROUND: Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. OBJECTIVES: We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients' clinical phenotypes. METHODS: We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. RESULTS: Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 µm2) and S groups (480 ± 135 µm2) compared with the N (1615 ± 388 µm2, both P < 0.05) and C groups (1219 ± 302 µm2, both P < 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. CONCLUSIONS: The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.


Assuntos
Autofagia , Caquexia/enzimologia , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sarcopenia/enzimologia , Neoplasias Gástricas/enzimologia , Adulto , Idoso , Caquexia/genética , Caquexia/patologia , Caquexia/fisiopatologia , Feminino , Humanos , Lisossomos/enzimologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/citologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Complexo de Endopeptidases do Proteassoma/genética , Sarcopenia/metabolismo , Sarcopenia/patologia , Sarcopenia/fisiopatologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/fisiopatologia , Ubiquitina/metabolismo
10.
Biochem Pharmacol ; 174: 113811, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954719

RESUMO

Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of pTyr105-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, pTyr105-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended in vivo, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear pTyr105-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.


Assuntos
Neoplasias Duodenais/enzimologia , Indóis/farmacologia , Nitrobenzenos/farmacologia , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/enzimologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Neoplasias Duodenais/tratamento farmacológico , Humanos , Indóis/uso terapêutico , Masculino , Metanol/análogos & derivados , Camundongos , Camundongos Nus , Nitrobenzenos/uso terapêutico , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Neoplasias Gástricas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
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
12.
Food Chem Toxicol ; 137: 111131, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31958483

RESUMO

To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Curcumina/análogos & derivados , MAP Quinase Quinase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , MAP Quinase Quinase 4/genética , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/fisiopatologia , Fatores de Transcrição/genética
13.
Mol Med Rep ; 21(2): 842-850, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974627

RESUMO

The present study investigated the role of cytochrome P450 family 2 subfamily E polypeptide 1 (CYP2E1) in the development and progression of gastric cancer (GC). The expression levels of CYP2E1 in MGC­803 GC cells and normal GES­1 cells were investigated via western blotting, and it was identified that the expression of CYP2E1 was different between GES­1 and MGC­803 cells. CYP2E1 was overexpressed in MGC­803 cells using a lentiviral vector GV358. Cell Counting Kit­8, flow cytometry, cell migration and Matrigel invasion assays suggested that overexpression of CYP2E1 promoted the proliferation and invasion, and inhibited the apoptosis of GC cells. The relationship between CYP2E1 expression and key signaling molecules in the PI3K/Akt/mTOR signaling pathway was assessed. Reverse transcription­quantitative PCR analysis showed that mTOR mRNA expression was significantly increased after overexpression of CYP2E1 (P<0.05). Western blotting results showed that overexpression of CYP2E1 upregulated the expression of phosphorylated (p)­Akt, p­mTOR and p­p70 ribosomal protein S6 kinase (P70S6K; Ser371) proteins (P<0.05). To further investigate the relationship between CYP2E1 and the PI3K/Akt/mTOR signaling pathway in GC cells, MGC­803 cells were treated with the PI3K inhibitor LY294002, and changes in the expression levels of PI3K, AKT, mTOR, P70S6K and CYP2E1 were observed. The present results showed that LY294002 downregulated the expression of PI3K, CYP2E1, AKT, mTOR and P70S6K (P<0.05). Therefore, changes in the biological function of GC cells induced by CYP2E1 overexpression may be via the PI3K/Akt/mTOR signaling pathway.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Citocromo P-450 CYP2E1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Lentivirus/metabolismo , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
14.
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
15.
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
16.
Am J Physiol Gastrointest Liver Physiol ; 318(1): G10-G22, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433213

RESUMO

Gastric cancer (GC) is one of the most common cancers in the world and remains a heavy burden of health worldwide. Adenylate cyclase 3 (ADCY3) is a widely expressed membrane-associated protein in human tissues and has been identified to be a new molecular target of GC. Long noncoding RNAs have a substantial influence on tumorigenesis and progression of tumors by binding to microRNAs. Therefore, this study is to clarify the mechanism by which LINC00319 sponges micro RNA-335-5p (miR-335-5p) to influence the development of GC. Initially, microarray analysis identified GC-related differentially expressed LINC00319 and ADCY3 for this study. The interaction was confirmed that LINC00319 interacted with miR-335-5p to regulate ADCY3. Next, SGC-7901 cells presenting with the lowest LINC00319 expression and the highest miR-335-5p expression were transfected with LINC00319, miR-335-5p inhibitor, or ADCY3 vector to examine their roles in growth and metastasis of GC cells, which was further ascertained by in vivo experiments. LINC00319 was upregulated and miR-335-5p was downregulated in GC cells. LINC00319 overexpression, miR-335-5p inhibitor, or ADCY3 overexpression was shown to significantly elevate the expression of cyclin-dependent kinase 4 and metastasis associated 1, decrease that of growth arrest-specific 1, and promote tumor growth and metastasis by increasing proliferation and migration and reducing cell apoptosis. Importantly, it was found that overexpressed miR-335-5p exerted its tumor suppressive role in GC through downregulating ADCY3. Collectively, LINC00319 expedited growth and metastasis of GC by upregulating miR-335-5p-mediated ADCY3.NEW & NOTEWORTHY This study is carried out based on in vivo and in vitro studies in mice and gastric cancer (GC) cells with the aim of clarifying the role of LINC00319 on GC growth and metastasis, which associated with micro RNA-335-5p-mediated adenylate cyclase 3. Altogether, we identified LINC00319 to be a potential therapy to treat GC.


Assuntos
Adenilil Ciclases/metabolismo , Movimento Celular , Proliferação de Células , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/enzimologia , Regiões 3' não Traduzidas , Adenilil Ciclases/genética , Animais , Apoptose , Sítios de Ligação , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Bases de Dados Genéticas , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , MicroRNAs/genética , Metástase Neoplásica , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transativadores/genética , Transativadores/metabolismo , Carga Tumoral , Regulação para Cima
17.
Dig Dis Sci ; 65(1): 168-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350707

RESUMO

PURPOSE: The interferon regulatory factor 2 (IRF-2) acted as a tumor suppressor. We inspected IRF-2 as a predictor of prognosis in gastric cancer (GC) patients and tried to find out the potential molecular mechanism. METHODS: In this study, the association between IRF-2 expression and clinical or prognosis significance was investigated in 86 pairs of tumor and the adjacent normal gastric tissues from GC patients. After establishing the stable cell lines, the Transwell assays were deduced to evaluate the malignancy of tumor. Then, microarray assay was carried out and the GO/KEGG pathway analyses were conducted to identify IRF-2's target gene. The relationship between IRF-2 and matrix metalloproteinases 1 (MMP-1) was also investigated by the immunohistochemistry in 15 pairs of tumor and adjacent normal gastric tissues. RESULTS: We found that IRF-2 expression level in GC was significantly correlated with the prognosis of the patients. Transwell assays suggested an impaired ability of invasion and migration in IRF-2-overexpressed GC cells and a progressive malignant phenotype in IRF-2-knockdown GC cells. Ninety differentially expressed genes were found between IRF-2-overexpressed GC cells and its normal control sets by microarray. We demonstrated that MMP-1 was canonical in the network of differentially expressed genes by GO and KEGG pathway analysis and its expression level was markedly decreased in IRF-2-overexpressed cells of MKN-45 and increased in IRF-2-knockdown cells of SGC-7901. The expression of MMP-1 was inversely correlated with IRF-2 in GAC TMA specimens. CONCLUSION: IRF-2 may inhibit GC progression by down-regulating MMP-1 level.


Assuntos
Movimento Celular , Fator Regulador 2 de Interferon/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Neoplasias Gástricas/enzimologia , Idoso , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fator Regulador 2 de Interferon/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
18.
Biochem Biophys Res Commun ; 521(4): 1003-1009, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31727367

RESUMO

Helicobacter pylori (H. pylori) infection can promote the development of gastric cancer (GC); however, the underlying mechanism is not clear. FAM60A has been found showing high levels in some cancer cells, including lung cancer (A549), and pancreatic cancer (Capan-2) cell lines. Data in oncomine showed that FAM60A overexpression was an critical prognostic factor in GC. In this study, we showed that knockdown of FAM60A could revert the increase of proliferation and the decrease of apoptosis caused by H.pylori infection in HGC-27 and AGS cells. Conversely, FAM60A upregulation promoted proliferation and inhibited apoptosis in HGC-27 and AGS cells. We also found that the PI3K/AKT pathway inhibitor LY294002 could revert the changes caused by FAM60A upregulation in HGC-27 and AGS cells. Thus, our study provides evidence that FAM60A act as a carcinogen and suggests that H. pylori-induced upregulation of FAM60A may contribute to the development of gastric cancer.


Assuntos
Apoptose/genética , Proteínas de Ligação a DNA/metabolismo , Helicobacter pylori/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Infecções por Helicobacter/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/microbiologia , Regulação para Cima/genética
19.
Sci Rep ; 9(1): 19084, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836775

RESUMO

Gastric cancer (GC) is one of the leading malignancies around the world. Identification of novel and efficient biomarkers for GC diagnosis and evaluation of therapeutic efficiency could improve the therapeutic strategy in future clinical application. This study aims to evaluate the levels of plasma thioredoxin reductase (TrxR) activity in GC patients to confirm its validity and efficacy in GC diagnosis and evaluation of therapeutic efficiency. 923 cases were enrolled in the current study. In the group of GC patients before clinical intervention, plasma TrxR activity [9.09 (7.96, 10.45) U/mL] was significantly higher than in healthy controls [3.69 (2.38, 5.32) U/mL]. The threshold of TrxR activity for GC diagnosis was set at 7.34 U/mL with a sensitivity of 85.5% and a specificity of 97.9%. In GC patients after chemotherapy, plasma TrxR activity was remarkably higher in patients with progressive disease or uncontrolled condition [10.07 (8.19, 11.02) U/mL] compared with patients with complete or partial response [7.12 (6.08, 8.37) U/mL] in response to chemotherapy. TrxR activity displayed the higher efficiency to distinguish between GC patients with two distinct clinical outcomes than carcinoembryonic antigen (CEA), cancer antigen 72-4 (CA72-4) and cancer antigen 19-9 (CA19-9). Moreover, combination of TrxR, CEA, CA72-4 and CA19-9 was demonstrated to be more effective in both GC diagnosis and evaluation of therapeutic efficiency than was each biomarker individually. Together, plasma TrxR activity was identified as a novel and efficient biomarker of GC, both in diagnosis and monitoring of therapeutic efficiency in response to chemotherapy.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Tiorredoxina Dissulfeto Redutase/sangue , Antígenos Glicosídicos Associados a Tumores/sangue , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Estudos de Casos e Controles , Humanos , Estadiamento de Neoplasias , Curva ROC , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico
20.
Lipids Health Dis ; 18(1): 203, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757214

RESUMO

BACKGROUND: A healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. Oxysterols provided from food or cholesterol oxidation in the gastric epithelium may be further sulfated by hydroxysteroid sulfotransferase 2B1 (SULT2B1), which is highly abundant in the gastric epithelium. However, the effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear. METHODS: A mouse gastric tumor model was established using carcinogenic agent 3-methylcholanthrene (3-MCA). A SULT2B1 deletion (SULT2B1-/-) human gastric epithelial line GES-1 was constructed by CRISPR/CAS9 genome editing system. RESULTS: The gastric tumor incidence was higher in the SULT2B1-/- mice than in the wild-type (WT) mice. In gastric epithelial cells, adenovirus-mediated SULT2B1b overexpression reduced the levels of oxysterols, such as 24(R/S),25-epoxycholesterol (24(R/S),25-EC) and 27-hydroxycholesterol (27HC). This condition also increased PI3K/AKT signaling to promote gastric epithelial cell proliferation, epithelization, and epithelial development. However, SULT2B1 deletion or SULT2B1 knockdown suppressed PI3K/AKT signaling, epithelial cell epithelization, and wound healing and induced gastric epithelial cell malignant transition upon 3-MCA induction. CONCLUSIONS: The abundant SULT2B1 expression in normal gastric epithelium might maintain epithelial function via the PI3K/AKT signaling pathway and suppress gastric carcinogenesis induced by a carcinogenic agent.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Sulfotransferases/genética , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Colesterol/análogos & derivados , Colesterol/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/enzimologia , Mucosa Gástrica/patologia , Edição de Genes , Humanos , Hidroxicolesteróis/metabolismo , Metilcolantreno/administração & dosagem , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/deficiência , Análise de Sobrevida
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