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1.
Rinsho Ketsueki ; 60(7): 818-823, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391372

RESUMO

Myelodysplastic syndromes (MDS), a group of heterogeneous hematopoietic disorders, are characterized by multi-lineage dysplasia and ineffective hematopoiesis. Despite identifying multiple gene mutations in patients with MDS, their main clinical features are similar. To resolve the discrepancy between genotypes and phenotypes, we performed transcriptome and epigenome analyses to ascertain the shared underlying mediator (s) of MDS etiology and identified HIF1A signaling as a central pathobiological mediator of MDS. HIF1A is a critical regulator for several physiological pathways associated with stem-cell maintenance, angiogenesis, glucose-metabolism, and immune activation. We identified dysregulated HIF1A signature in human patients with MDS. Using mouse genetic models, we demonstrated that the dysregulation of HIF1A could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS-driver mutations. The genetic disruption of HIF1A resolves MDS phenotypes. These findings suggest that HIF1A is an effective therapeutic target for a broad spectrum of patients with MDS.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndromes Mielodisplásicas/genética , Animais , Hematopoese , Humanos , Camundongos , Mutação , Transdução de Sinais , Transcriptoma
2.
Anticancer Res ; 39(8): 4165-4170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366501

RESUMO

AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow. MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined. RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation. CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucemia/genética , Receptor Notch1/genética , Ciclo Celular/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Leucemia/patologia , NF-kappa B/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
3.
J Agric Food Chem ; 67(32): 8855-8867, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343893

RESUMO

Abalone (Haliotis discus hannai) is a precious seafood in the market. It has been reported that biological active substances derived from abalone have anti-oxidative, anti-inflammatory, anti-bacterial, and anti-thrombosis potential. However, there were few studies to assess whether they have anti-cancer potential. In this study, we evaluated the anti-metastasis and anti-pro-angiogenic factors and mechanism of action of boiled abalone byproduct peptide (BABP, EMDEAQDPSEW) in human fibrosarcoma (HT1080) cells and human umbilical vein endothelial cells (HUVECs). The results demonstrated that BABP treatment significantly lowers migration and the invasion of HT1080 cells and HUVECs. BABP inhibits phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase (MMP) expression and activity by blocking mitogen-activated protein kinases (MAPKs) and NF-κB signaling and hypoxia-induced vascular endothelial growth factor (VEGF) secretion and hypoxia inducible factor (HIF)-1α accumulation through suppressing the AKT/mTOR signal pathway. BABP treatment inhibits VEGF-induced VEGFR-2 expression and tube formation in HUVECs. The effect of BABP on anti-metastatic and anti-vascular activity in HT1080 cells and HUVECs revealed that BABP may be a potential pharmacophore for tumor therapy in the future.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Gastrópodes/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Peptídeos/farmacologia , Resíduos/análise , Inibidores da Angiogênese/química , Inibidores da Angiogênese/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Peptídeos/química , Peptídeos/isolamento & purificação , Frutos do Mar/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 199-203, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257798

RESUMO

OBJECTIVE: To analyze the expression and relationship of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR) in local skin tissues of pressure injury and investigate the possible mechanism of stage 3 pressure injury refractory wound. METHODS: Forty male SD rats were randomly divided into normal control group, compressed 3 d, 5 d, 7 d, and 9 d groups. Stage 3 pressure injury animal model were established by magnet compression. The morphology of skin was observed by HE staining. The expression of VEGF was detected by immunohistochemistry. The expression levels of HIF-1α, VEGF and KDR protein in skin tissue were detected by Western blot. One-way analysis of variance and LSD test were performed on the data. RESULTS: ①The HE results showed that compared with the normal control group, the epidermis of the compressed group was gradually thickened, the number of blood vessels was decreased, the collagen arrangement disordered and inflammatory cells infiltration were increased. ②Immunohistochemical results showed that the expression of VEGF protein in the 3 d group was significantly higher than that in the normal control group (P<0.01). The expression of VEGF protein in the skin tissue of 5 d, 7 d and 9 d groups was lower than that in normal control group (P<0.05). WB results were consistent with immunohistochemistry results. ③WB results showed that the expression of HIF-1α in the skin tissues of the rats in 3 d, 5 d and 7 d groups was higher than that in the normal control group (P<0.01 or P<0.05). The expression of KDR protein was lower than that of the normal control group (P<0.05 or P<0.01). CONCLUSION: HIF-1α mediated reduction of VEGF and KDR protein expression and decreased tissue angiogenesis may be one of the important causes of chronic dysfunction of stage 3 pressure injury.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pressão/efeitos adversos , Pele/lesões , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
5.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
6.
Int Heart J ; 60(4): 964-973, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257333

RESUMO

Acute myocardial infarction (AMI) is a serious heart disease and the main reason for heart failure and sudden death worldwide. This study investigated the effects of polysaccharides from Enteromorpha prolifera (PEP) on AMI in vitro and in vivo, as well as the underlying mechanisms.Human cardiac microvascular endothelial cells (HCMVEC) were cultured in vitro in an oxygen-glucose deprivation (OGD) environment to induce injury. The viability and apoptosis of HCMVEC were then detected using CCK-8 assay and Annexin V-FITC/PI staining, respectively. ELISA was performed to measure the concentrations of inflammatory cytokines. Cell transfection was conducted to reduce the expression of HIF-1α. Expression of key factors involving in cell proliferation, apoptosis, autophagy, MEK/ERK, and the NF-κB and mTOR pathways were evaluated using Western blotting. In vivo, Wistar rats were pre-treated by PEP and AMI was induced. The infarct size and cardiac functions (LVEDD, LVEF and LVFS) were measured.In vitro, PEP treatment significantly protected HCMVEC from OGD-induced viability loss, proliferation inhibition, apoptosis, inflammatory cytokine expression, and autophagy. Moreover, PEP enhanced the expression of HIF-1α in HCMVEC via the MEK/ERK pathway. HIF-1α participated in the protective effects of PEP on OGD-treated HCMVEC. Furthermore, PEP attenuated OGD-induced NF-κB pathway activation and promoted the mTOR pathway in HCMVEC. In vivo, PEP pre-treatment reduced the infarct size and enhanced the LVEDD, LVEF and LVFS of rats via up-regulation of HIF-1α.PEP ameliorated AMI in vitro and in vivo through up-regulation of HIF-1α. In vitro, PEP could activate the MEK/ERK and mTOR pathways, but inactivate the NF-κB pathway in OGD-treated HCMVEC.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Infarto do Miocárdio/genética , Polissacarídeos Bacterianos/farmacologia , RNA/genética , Regulação para Cima , Animais , Apoptose , Western Blotting , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais
7.
Nat Commun ; 10(1): 2824, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249305

RESUMO

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-ß1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-ß1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-ß1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.


Assuntos
Fibrose/metabolismo , Hipóxia/metabolismo , Macrófagos/metabolismo , Oncostatina M/metabolismo , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oncostatina M/genética , Fosforilação , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
8.
Gene ; 711: 143938, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31220580

RESUMO

BACKGROUND AND PURPOSE: The pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor. METHODS: Formalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα+/PR+) from those with a poorer prognosis (ERα-/PR-). Immunohistochemistry for HIF1-α and SLUG was also performed. Body mass index (BMI) was registered at the time of diagnosis: patients with BMI ≥ 30 kg/m2 were defined obese (OB). Total RNA was isolated for miR-221 analysis. RESULTS: We showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα+/PR+ and ERα-/PR- groups. However, the obesity factor impacted more in the ERα+/PR+ group since the ratio between OB and non-obese (NOB) patients with high expression of HIF1-α and SLUG was higher in ERα+/PR+ than in the ERα-/PR- group. miR-221 levels were significantly higher in the OB than NOB patients, and, also in this case, obesity impacted more in the ERα+/PR+ group. CONCLUSIONS: A molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.


Assuntos
Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Obesidade/genética , Receptores de Progesterona/metabolismo , Fatores de Transcrição da Família Snail/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Obesidade/metabolismo , Estudos Retrospectivos , Fatores de Risco , Fatores de Transcrição da Família Snail/metabolismo , Microambiente Tumoral
9.
J Agric Food Chem ; 67(28): 7844-7854, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241937

RESUMO

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 µM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isotiocianatos/administração & dosagem , Neoplasias da Bexiga Urinária/fisiopatologia , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
10.
Int Heart J ; 60(4): 924-937, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204374

RESUMO

Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.


Assuntos
Hipertensão Pulmonar/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-sis/genética , Embolia Pulmonar/complicações , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Embolia Pulmonar/genética , Embolia Pulmonar/metabolismo
11.
Cancer Sci ; 110(8): 2368-2377, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222863

RESUMO

Macrophages are essential inflammatory cells which regulate the features of immune reactions within tumors. Many studies have reported their regulatory roles in immunity through cytokines and cell signaling. However, relatively few studies have focused on their metabolic features and mechanisms. We aimed to determine the signaling pathway regulating cell metabolism and the mechanism related to the regulation of human tumor-associated macrophages (TAMs) in gastric cancer (GC). Tumor-infiltrated macrophages were isolated from human GC tissues using magnetic beads, gene transcription was determined by real-time PCR, protein expression was monitored using western blots, metabolites were determined using HPLC, and transcriptional regulation was analyzed by the luciferase-based reporter gene system. A significant decrease in microRNA (miR)-30c and an increase in regulated in development and DNA damage responses 1 (REDD1) were detected in human GC TAMs, the transcription of miR-30c was negatively correlated with REDD1. MicroRNA-30c expression was suppressed by hypoxia-inducible factor-1α activation and related to decreased mTOR activity as well as glycolysis in human GC TAMs. Hypoxia-regulated miR-30c downregulated REDD-1 expression by targeting its 3'UTR. Overexpression of miR-30c or restored mTOR activity in macrophages with miR-30cLow expression promoted M1 macrophage differentiation and function in TAMs. Therefore, hypoxia in the human GC microenvironment suppressed the expression of miR-30c, and decreased mTOR activity as well as glycolysis in GC TAMs, thus inhibiting M1 differentiation and function. These results provide a novel metabolic strategy for tumor microenvironment-based therapy.


Assuntos
Glicólise/genética , Hipóxia/genética , Macrófagos/patologia , MicroRNAs/genética , Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/genética , Regiões 3' não Traduzidas/genética , Diferenciação Celular , Linhagem Celular , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Fatores de Transcrição/genética , Transcrição Genética/genética , Microambiente Tumoral/genética
12.
Life Sci ; 232: 116601, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31252000

RESUMO

AIMS: Tet1, Tet2, and interleukin-6 (IL-6) have been linked to atherosclerosis. Whether Tet3 has a relationship with atherosclerosis and IL-6 was unknown. This study aims to determine the link between Tet3 and IL-6, and the role of Tet3 in prenatal hypoxia-induced atherosclerosis in offspring rats. MAIN METHODS: Pregnant rats were divided into hypoxia and control group. Their male offspring were tested at 20 months old. Hematoxylin-eosin staining and transmission electron microscopic staining were used. Gene mRNA and protein levels were measured with q-PCR or Western blotting. Cell viability and migration was tested with MTT or cell scratch assay. 5-hmC and 5-mC expression were obtained by qGlucMS-PCR; 5-hmC and 5-mC activity were obtained by dot blotting. KEY FINDINGS: Chronic prenatal hypoxia increased Tet3 and IL-6 expression, and decreased Tet3 activity in offspring rats. GlucMS-qPCR showed the percentage of 5-hmC was significantly up-regulated in the promoter of IL-6 in both the rats and cells. Moreover, 5-hmC percentage also was increased in the A7r5 cells transfected with Tet3. Furthermore, Tet3 promoted proliferation and migration of A7r5 cells. However, Tet3 was not sensitive to acute hypoxia, while influenced by HIF-1α DNA element. SIGNIFICANCE: Tet3 enhanced IL-6 expression though up-regulating 5-hmC percentage in the IL-6 promoter.


Assuntos
Aterosclerose/metabolismo , Desoxicitidina/análogos & derivados , Dioxigenases/metabolismo , Hipóxia/metabolismo , Interleucina-6/biossíntese , Animais , Aterosclerose/genética , Aterosclerose/patologia , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Desoxicitidina/metabolismo , Epigênese Genética , Feminino , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Oxigenases de Função Mista/metabolismo , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ativação Transcricional , Regulação para Cima
13.
Cell Mol Biol Lett ; 24: 28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061665

RESUMO

Background: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor with a pivotal role in physiological and pathological responses to hypoxia. While HIF-1α is known to be involved in hypoxia-induced upregulation of microRNA (miRNA) expression, HIF-1α is also targeted by miRNAs. In this study, miRNAs targeting HIF-1α were identified and their effects on its expression and downstream target genes under hypoxic conditions were investigated. Cell migration under the same conditions was also assessed. Methods: microRNAs that target HIF-1α were screened using 3'-untranslated region luciferase (3'-UTR-luciferase) reporter assays. The expression levels of HIF-1α and its downstream target genes after transfection with miRNA were assessed using quantitative RT-PCR and western blot analyses. The effect of the miRNAs on the transcriptional activity of HIF-1α was determined using hypoxia-responsive element luciferase (HRE-luciferase) assays. Cell migration under hypoxia was examined using the wound-healing assay. Results: Several of the 19 screened miRNAs considerably decreased the luciferase activity. Transfection with miR-200c had substantial impact on the expression level and transcription activity of HIF-1α. The mRNA level of HIF-1α downstream genes decreased in response to miR-200c overexpression. MiR-200c inhibited cell migration in normoxia and, to a greater extent, in hypoxia. These effects were partly reversed by HIF-1α expression under hypoxic conditions. Conclusion: miR-200c negatively affects hypoxia-induced responses by downregulating HIF-1α, a key regulator of hypoxia. Therefore, overexpression of miR-200c might have therapeutic potential as an anticancer agent that inhibits tumor hypoxia.


Assuntos
Movimento Celular/genética , Regulação para Baixo/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Sequência de Bases , Hipóxia Celular/genética , Linhagem Celular Tumoral , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Luciferases/metabolismo , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética , Regulação para Cima/genética , Cicatrização
14.
Nat Commun ; 10(1): 2126, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073164

RESUMO

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. However, the mechanisms of endothelial regeneration remain poorly understood. Here we show that the endothelial and hematopoietic developmental transcription factor Sox17 promotes endothelial regeneration in the endotoxemia model of endothelial injury. Genetic lineage tracing studies demonstrate that the native endothelium itself serves as the primary source of endothelial cells repopulating the vessel wall following injury. We identify Sox17 as a key regulator of endothelial cell regeneration using endothelial-specific deletion and overexpression of Sox17. Endotoxemia upregulates Hypoxia inducible factor 1α, which in turn transcriptionally activates Sox17 expression. We observe that Sox17 increases endothelial cell proliferation via upregulation of Cyclin E1. Furthermore, endothelial-specific upregulation of Sox17 in vivo enhances lung endothelial regeneration. We conclude that endotoxemia adaptively activates Sox17 expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis.


Assuntos
Ciclina E/genética , Endotélio Vascular/fisiopatologia , Endotoxemia/patologia , Proteínas HMGB/metabolismo , Proteínas Oncogênicas/genética , Regeneração/imunologia , Fatores de Transcrição SOXF/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Ciclina E/metabolismo , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Endotoxemia/imunologia , Células HEK293 , Proteínas HMGB/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição SOXF/genética , Transdução de Sinais/fisiologia , Regulação para Cima
15.
J Ovarian Res ; 12(1): 42, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077234

RESUMO

BACKGROUND: Chemokines are involved in the homing of various cancer cells, including those of ovarian cancer (OvCa), to distant organs. They may also promote or inhibit cancer progression and metastasis. Hypoxia, a common phenomenon in malignant tumors, promotes cell proliferation regulated by HIF-1α. Hypoxia-induced genes are involved in metastasis-associated functions and in the epithelial-to-mesenchymal transition (EMT). RESULTS: Tissue microarrays of human OvCa showed elevated expression of CX3CR1 and HIF-1α compared to normal cells, and their levels were higher in adenocarcinoma stages II and III. To substantiate these observations, we performed studies using OvCa cells. Following exposure to hypoxia, OVCAR-3, SW 626, and TOV-112D cells showed high expression of CX3CR1, a transmembrane protein involved in the adhesion and migration of leukocytes, causing an increased chemotactic response to CX3CL1, the ligand for CX3CR1. As determined by flow cytometry, immunofluorescence, RT-PCR, and western blots, there were higher expressions of CX3CR1 and HIF-1α in OvCa cell lines exposed to hypoxia. Further, OvCa cells expressing CX3CR1 were sensitive to the CX3CL1 ligand. Chemotaxis based on chemokine receptors was influential in elevating the expression of EMT markers and matrix metalloproteinases, which are involved in the progression and metastasis of cancer cells. CONCLUSIONS: In OvCa cells, CX3CR1 was upregulated in a process involving hypoxia-mediated regulation of HIF-1α. The elevated levels of CX3CR1, which were sensitive to CX3CL1, increased EMT markers that led to the progression and metastasis of OvCa. Thus, CX3CR1 and HIF-1α are suitable targets for treatment of OvCa.


Assuntos
Receptor 1 de Quimiocina CX3C/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor 1 de Quimiocina CX3C/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Quimiocina CX3CL1/biossíntese , Quimiocina CX3CL1/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Invasividade Neoplásica , Neoplasias Ovarianas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Mol Med Rep ; 19(6): 5335-5344, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059047

RESUMO

MicroRNAs (miRs) have been identified as critical regulatory molecules in myocardial ischemia/reperfusion injury; however, the exact expression profile of miR­199a­5p in reperfusion injury and the underlying pathogenic mechanisms remain unclear. In the present study, it was revealed that miR­199a­5p expression was significantly increased in the plasma of patients with acute myocardial infarction and in a H9c2 cell model of oxygen­glucose deprivation and reperfusion (OGD/R) via reverse transcription­quantitative PCR. H9c2 cells were transfected with miR­199a­5p mimic or inhibitor, or short interfering RNA (siRNA) specific to hypoxia­inducible factor­1α (HIF­1α). MTS, lactate dehydrogenase (LDH), TUNEL staining and flow cytometry assays were performed to determine the proliferation, LDH activity, apoptosis and mitochondrial membrane potential (ΔΨm) of H9c2 cells, respectively. The overexpression of miR­199a­5p in the OGD/R cell model significantly decreased the viability and increased the lactate dehydrogenase leakage of cells; whereas knockdown of miR­199­5p induced the opposing effects. Additionally, inhibition of miR­199­5p significantly attenuated OGD/R­induced alterations to the mitochondrial transmembrane potential (ΔΨm) and increases in the apoptosis of cells. Furthermore, the overexpression or knockdown of miR­199a­5p decreased or increased the expression of HIF­1α and phosphorylation of glycogen synthase kinase 3ß (GSK3ß) in OGD/R­treated H9c2 cells. Additionally, siRNA­mediated downregulation of HIF­1α decreased phosphorylated (p)­GSK3ß (Ser9) levels and reversed the protective effects of miR­199a­5p inhibition on OGD/R­injured H9c2 cells. Similarly, treatment with LiCl (a specific inhibitor of p­GSK3ß) also attenuated the protective effects of miR­199a­5p knockdown on OGD/R­injured H9c2 cells. Mechanistic studies revealed that HIF­1α was a target of miR­199a­5p, and that HIF­1α downregulation suppressed the expression of p­GSK3ß in OGD/R­injured H9c2 cells. Furthermore, an miR­199a­5p inhibitor increased the interaction between p­GSK3ß and adenine nucleotide transferase (ANT), which was decreased by OGD/R. Additionally, miR­199a­5p inhibitor reduced the OGD/R­induced interaction between ANT and cyclophilin D (Cyp­D), potentially leading to the increased mitochondrial membrane potential in inhibitor­transfected OGD/R­injured H9c2 cells. Collectively, the present study identified a novel regulatory pathway in which the upregulation of miR­199a­5p reduced the expression of HIF­1α and p­GSK3ß, and potentially suppresses the interaction between p­GSK3ß and ANT, thus promoting the interaction between ANT and Cyp­D and potentially inducing cytotoxicity in OGD/R­injured H9c2 cells.


Assuntos
Hipóxia Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/patologia , Adulto , Animais , Antagomirs/metabolismo , Sobrevivência Celular , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Potencial da Membrana Mitocondrial , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais
17.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 48-52, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078152

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Compound K, an active metabolite of ginsenosides, is reported to exhibit anti-cancer property in various types of human malignancies. The present study investigated the role of compound K on glucose metabolism in NSCLC cells and its underlying mechanism. Our study found that compound K dose-dependently inhibited the cell viability of NSCLC cells. Moreover, administration with compound K decreased glucose uptake and lactate secretion under normoxic and hypoxic conditions. Consistently, the expression of key enzymes (HK II, PDK1 and LDHA) involved in glucose metabolism were inhibited in compound K-treated tumor cells. In addition, compound K inhibited the expression of HIF-1α and its downstream gene GLUT1. On the contrary, overexpression of HIF-1α elevated metabolic reactions and partly attenuated the inhibitory role of compound K on NSCLC cell growth. These results demonstrate that compound K suppresses NSCLC cell growth via HIF-1α mediated metabolic alteration, contributing to novel anticancer therapy by targeting glucose metabolism.


Assuntos
Ginsenosídeos/farmacologia , Glucose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética
18.
Mol Med Rep ; 19(6): 4935-4945, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059086

RESUMO

Previous reports have indicated a potential link between microRNA (miR)­214 and hypoxia. In the present study, the biological functions and potential mechanisms of miR­214 were determined, as well as its correlation with HIF­1α signaling in non­small cell lung cancer (NSCLC) cells. Quantitative polymerase chain reaction revealed that miR­214 expression was upregulated in lung cancer tissues compared with adjacent normal tissues. miR­214 mimics were transfected into A549 cells, and MTT, colony formation, invasion and wound healing assays were performed. It was demonstrated that miR­214 mimic transfection promoted the invasion, proliferation and migration of A549 cells. Furthermore, miR­214 inhibitor transfection decreased H1299 cell invasion, proliferation and migration. Next, the association between miR­214 expression and the HIF­1α signaling cascade was examined. It was demonstrated that miR­214 mimics upregulated the expression of hypoxia­inducible factor (HIF)­1α, vascular endothelial growth factor (VEGF), adenylate kinase 3 and matrix metalloproteinase (MMP)2, whereas miR­214 inhibitor downregulated the expression of these factors. Using prediction software, it was demonstrated that tumor suppressor ING4 was a target of miR­214. A luciferase reporter assay confirmed that ING4 was a direct target of miR­214. There was a negative correlation between ING4 and miR­214 expression in lung cancer tissues. In addition, ING4 siRNA and plasmid was transfected into cells in order to validate its effect on HIF­1α, MMP2 and VEGF expression. ING4 overexpression downregulated HIF­1α and its targets MMP2 and VEGF, while ING4 siRNA upregulated HIF­1α, MMP2 and VEGF. In conclusion, it was demonstrated that miR­214 targeted ING4 in lung cancer cells, and upregulated the HIF­1α cascade, leading to MMP2 and VEGF upregulation. This approach may help to clarify the role of miRNA in non­small lung cancer and may be a new therapeutic target for non­small lung cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Homeodomínio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células A549 , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Adulto , Idoso , Antagomirs/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Fator A de Crescimento do Endotélio Vascular/genética
19.
J Stroke Cerebrovasc Dis ; 28(6): 1540-1545, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30952532

RESUMO

BACKGROUND: Stroke is one of the leading causes of morbidity and mortality. Thromboembolism, as a major cause of carotid artery-related stroke, can be caused by plaque rupture which is associated with neoangiogenesis within the carotid plaque. AIM: We sought to investigate a possible correlation between angiogenesis-related factors and preoperative neurological manifestations in patients with internal carotid artery stenosis, for a better understanding of thromboembolism in internal carotid artery stenosis-related stroke. METHODS: This study included 54 patients (asymptomatic, n = 20 and symptomatic, n = 34) undergoing carotid endarterectomy for high-grade internal carotid artery stenosis. In the retrieved carotid plaques, angiogenesis-related factors (vascular endothelial growth factor [VEGF], hypoxia inducible factor-1 alpha [HIF-1α], and Clusterin) were measured by immunohistochemistry and quantified by real-time polymerase chain reaction. RESULTS: We demonstrated the expression of VEGF, HIF-1α, and Clusterin by endothelial cells and smooth muscle cells in the carotid plaques. Noteworthy, mRNA VEGF levels were .7-fold higher in symptomatic patients (P = .017) compared to asymptomatic patients. In contrast, mRNA Clusterin levels were 1.8-fold lower (P = .021). Levels of mRNA HIF-1α were 1.5-fold higher in asymptomatic patients, but no statistical significance was reached between the 2 groups. CONCLUSIONS: Our results show an association between VEGF and Clusterin and neurological symptoms of patients with high-grade carotid artery stenosis.


Assuntos
Artéria Carótida Interna/química , Estenose das Carótidas/metabolismo , Clusterina/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Placa Aterosclerótica , Fator A de Crescimento do Endotélio Vascular/análise , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Artéria Carótida Interna/patologia , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/patologia , Estenose das Carótidas/cirurgia , Clusterina/genética , Feminino , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Estudos Prospectivos , RNA Mensageiro/genética , Ruptura Espontânea , Índice de Gravidade de Doença , Acidente Vascular Cerebral/etiologia , Fator A de Crescimento do Endotélio Vascular/genética
20.
Gene ; 704: 42-48, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980943

RESUMO

Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced ß-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/ß-catenin/VEGF axis in GC.


Assuntos
Gastrinas/farmacologia , Neovascularização Patológica/induzido quimicamente , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Gastrinas/fisiologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Oxigênio/farmacologia , Oxigênio/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
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