Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.175
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361045

RESUMO

Phosphoinositides (PIs) play important roles in the structure and function of the brain. Associations between PIs and the pathophysiology of schizophrenia have been studied. However, the significance of the PI metabolic pathway in the pathology of schizophrenia is unknown. We examined the expression of PI signaling-associated proteins in the postmortem brain of schizophrenia patients. Protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA, also known as PIK4A), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), protein kinase B (Akt), and glycogen synthase kinase 3ß (GSK3ß) were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays of the prefrontal cortex (PFC) of postmortem samples from 23 schizophrenia patients and 47 normal controls. We also examined the association between PIK4CA expression and its genetic variants in the same brain samples. PIK4CA expression was lower, whereas Akt expression was higher, in the PFC of schizophrenia patients than in that of controls; PIP5K1C, PTEN, and GSK3ß expression was not different. No single-nucleotide polymorphism significantly affected protein expression. We identified molecules involved in the pathology of schizophrenia via this lipid metabolic pathway. These results suggest that PIK4CA is involved in the mechanism underlying the pathogenesis of schizophrenia and is a potential novel therapeutic target.


Assuntos
Fosfatidilinositóis/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , 1-Fosfatidilinositol 4-Quinase/metabolismo , Idoso , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
2.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445559

RESUMO

Scutellarein (SCU) is a well-known flavone with a broad range of biological activities against several cancers. Human hepatocellular carcinoma (HCC) is major cancer type due to its poor prognosis even after treatment with chemotherapeutic drugs, which causes a variety of side effects in patients. Therefore, efforts have been made to develop effective biomarkers in the treatment of HCC in order to improve therapeutic outcomes using natural based agents. The current study used SCU as a treatment approach against HCC using the HepG2 cell line. Based on the cell viability assessment up to a 200 µM concentration of SCU, three low-toxic concentrations of (25, 50, and 100) µM were adopted for further investigation. SCU induced cell cycle arrest at the G2/M phase and inhibited cell migration and proliferation in HepG2 cells in a dose-dependent manner. Furthermore, increased PTEN expression by SCU led to the subsequent downregulation of PI3K/Akt/NF-κB signaling pathway related proteins. In addition, SCU regulated the metastasis with EMT and migration-related proteins in HepG2 cells. In summary, SCU inhibits cell proliferation and metastasis in HepG2 cells through PI3K/Akt/NF-κB signaling by upregulation of PTEN, suggesting that SCU might be used as a potential agent for HCC therapy.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células Tumorais Cultivadas
3.
Nat Commun ; 12(1): 5053, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417459

RESUMO

Previous studies have suggested that PTEN loss is associated with p110ß signaling dependency, leading to the clinical development of p110ß-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Humanos , Isoenzimas/metabolismo , Masculino , Camundongos , Modelos Biológicos , Organoides/efeitos dos fármacos , Organoides/metabolismo , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Medicine (Baltimore) ; 100(30): e26779, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397726

RESUMO

ABSTRACT: Angiosarcoma is a rare, highly aggressive malignant tumor originating from endothelial cells that line the lumen of blood or lymphatic vessels. The molecular mechanisms of scalp and face angiosarcoma still need to be elucidated. This study aimed to investigate the expression of phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphorylated mitogen-activated kinase-like protein (pMAPK), and tumor protein p53 (TP53) in scalp and face angiosarcoma and to assess tumor tissue apoptosis.The expression and intracellular distribution of PTEN, PIK3CA, pMAPK, and TP53 proteins in 21 specimens of human scalp and face angiosarcoma and 16 specimens of human benign hemangioma were evaluated using immunohistochemistry. Tumor cell apoptosis was assessed by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling staining.Significantly lower PTEN but higher PIK3CA, pMAPK, and TP53 immunostaining were detected in the angiosarcoma specimens than in the benign hemangioma specimens(P < .01). The angiosarcoma tissues exhibited significantly higher apoptosis indices than the benign hemangioma tissues (P < .01). The positive expression rates of PIK3CA, pMAPK, and TP53 were correlated with the degree of tumor differentiation in the human scalp and face angiosarcoma.The PI3K, MAPK, and TP53 pathways might be involved in angiosarcoma tumorigenesis in humans and may serve as therapeutic targets for the effective treatment of this malignancy.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Hemangiossarcoma/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo
5.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299331

RESUMO

BACKGROUND: Due to its prominence in the regulation of metabolism and inflammation, adipose tissue is a major target to investigate alterations in insulin action. This hormone activates PI3K/AKT pathway which is essential for glucose homeostasis, cell differentiation, and proliferation in insulin-sensitive tissues, like adipose tissue. The aim of this work was to evaluate the impact of chronic and intermittent high glucose on the expression of biomolecules of insulin signaling pathway during the differentiation and maturation of human visceral preadipocytes. METHODS: Human visceral preadipocytes (HPA-V) cells were treated with high glucose (30 mM)during the proliferation and/or differentiation and/or maturation stage. The level of mRNA (by Real-Time PCR) and protein (by Elisa tests) expression of IRS1, PI3K, PTEN, AKT2, and GLUT4 was examined after each culture stage. Furthermore, we investigated whether miR-29a-3p, miR-143-3p, miR-152-3p, miR-186-5p, miR-370-3p, and miR-374b-5p may affect the expression of biomolecules of the insulin signaling pathway. RESULTS: Both chronic and intermittent hyperglycemia affects insulin signaling in visceral pre/adipocytes by upregulation of analyzed PI3K/AKT pathway molecules. Both mRNA and protein expression level is more dependent on stage-specific events than the length of the period of high glucose exposure. What is more, miRs expression changes seem to be involved in PI3K/AKT expression regulation in response to hyperglycemic stimulation.


Assuntos
Hiperglicemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Hiperglicemia/patologia , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
6.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328194

RESUMO

Previous studies have suggested that oxidative stress and autophagy results in acute kidney injury (AKI) during sepsis and microRNA (miR)­214 serves a vital role in the protection of kidneys subjected to oxidative stress. The present study aimed to test whether the renoprotection of miR­214 is related to autophagy in sepsis. The role of autophagy was investigated in a mouse model of cecal ligation and puncture (CLP). Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to analyze the expression of miR­214. The structure and function of kidneys harvested from the mice were evaluated. Kidney autophagy levels were detected with immunohistochemical, immunofluorescent and western blotting. It was found that miR­214 could alleviate AKI in septic mice by inhibiting the level of kidney autophagy. Furthermore, miR­214 inhibited autophagy by silencing PTEN expression in the kidney tissues of septic mice. These findings indicated that miR­214 ameliorated CLP­induced AKI by reducing oxidative stress and inhibiting autophagy through the regulation of the PTEN/AKT/mTOR pathway.


Assuntos
Injúria Renal Aguda/genética , Autofagia/genética , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Ceco/lesões , Ceco/microbiologia , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Rim/ultraestrutura , Ligadura , Masculino , Camundongos , Estresse Oxidativo/genética , PTEN Fosfo-Hidrolase/genética , Punções , Sepse/complicações , Transdução de Sinais/genética
7.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207376

RESUMO

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.


Assuntos
Curcumina/farmacologia , Proteína Forkhead Box O3/metabolismo , Oócitos/efeitos dos fármacos , Reserva Ovariana , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/citologia , Oócitos/metabolismo , Oogênese , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Transdução de Sinais , Análise de Célula Única , Transcriptoma
8.
Nat Commun ; 12(1): 3707, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140478

RESUMO

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600E PtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.


Assuntos
Carcinogênese/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Proteínas de Homeodomínio/metabolismo , Melanoma/metabolismo , Fatores do Domínio POU/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Estudos de Coortes , Variações do Número de Cópias de DNA , Progressão da Doença , Técnicas de Silenciamento de Genes , Haploinsuficiência , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Fator de Transcrição Associado à Microftalmia/metabolismo , Mutação , Fatores do Domínio POU/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , RNA Interferente Pequeno , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário
9.
Cancer Sci ; 112(8): 3278-3292, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091997

RESUMO

It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2 O2 ) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2 O2 in LUAD cells and that the AQP3-dependent transport of H2 O2 accelerated cell growth and inhibited rapamycin-induced autophagy. Mechanistically, AQP3-mediated H2 O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3-induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Aquaporina 3/genética , Aquaporina 3/metabolismo , Peróxido de Hidrogênio/metabolismo , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
10.
Aging (Albany NY) ; 13(12): 16165-16177, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34114972

RESUMO

The occurrence of hypoxia-ischemia (HI) in the developing brain is closely associated with neuronal injury and even death. However, the underlying molecular mechanism is not fully understood. This study was designed to investigate phosphatase and tensin homolog (PTEN) nuclear translocation and its possible role in rat cortical neuronal damage following oxygen-glucose deprivation (OGD) in vitro. An in vitro OGD model was established using primary cortical neurons dissected from newborn Sprague-Dawley rats to mimic HI conditions. The PTENK13R mutant plasmid, which contains a lysine-to-arginine mutation at the lysine 13 residue, was constructed. The nuclei and cytoplasm of neurons were separated. Neuronal injury following OGD was evidenced by increased lactate dehydrogenase (LDH) release and apoptotic cell counts. In addition, PTEN expression was increased and the phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1/2) and activation of nuclear factor kappa B (NF-κB) were decreased following OGD. PTENK13R transfection prevented PTEN nuclear translocation; attenuated the effect of OGD on nuclear p-ERK1/2 and NF-κB, apoptosis, and LDH release; and increased the expression of several anti-apoptotic proteins. We conclude that PTEN nuclear translocation plays an essential role in neuronal injury following OGD via modulation of the p-ERK1/2 and NF-κB pathways. Prevention of PTEN nuclear translocation might be a candidate strategy for preventing brain injury following HI.


Assuntos
Núcleo Celular/metabolismo , Isquemia/metabolismo , Isquemia/patologia , NF-kappa B/metabolismo , Neurônios/patologia , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Animais , Hipóxia Celular , Células Cultivadas , Glucose/deficiência , Sistema de Sinalização das MAP Quinases , Neurônios/metabolismo , Oxigênio , Fosforilação , Transporte Proteico , Ratos Sprague-Dawley
11.
Artigo em Chinês | MEDLINE | ID: mdl-34074076

RESUMO

Objective: To screen and identify plasma differentially expressed genes and related signal pathway by human gene expression profile array and fluorescent quantitative PCR. Methods: From September 2018 to October 2019, 291 workers from a Mercury-in-glass thermometer factory in Jiangsu Province were selected for an occupational health examination, a total of 60 persons were divided into two groups: high and low mercury exposure groups (30 persons in each group) . Plasma total RNA samples from the high exposure group and the low exposure group (10 cases each) were detected by gene expression microarray, and differentially expressed genes (DEGs) with fold change >2 were selected. DEGs were submitted to David and Metascape for gene function clustering, pathway and protein interaction network analysis. Finally, fluorescence quantitative PCR was performed to verify the changes in the expression levels of key DEGs in the high exposure group and the low exposure group (another 20 cases in each group) . Results: A total of 269 DEGs, of which 203 up regulated and 66 down regulated were identified in the differential expression analysis of gene expression microarray. Bioinformatics analysis suggested that, DEGs were involved in forebrain development, glial cell fate determinants of GO biological process and PID NF-KB, PTEN signal pathway. NFE2L1, SOX8, SOX6 and RNF2 (P<0.05) were confirmed down regulated in high level group by fluorescent quantitative PCR compared with the low level group (fold changes were 2.10, 11.52, 2.19, and 4.38 respectively) . Conclusion: The plasma NFE2L1, SOX8, SOX6 and RNF2 gene expressions are significantly altered in occupa tional high mercury exposure population. PTEN signaling pathway and fate of glia cells determines the biological process may be closely related to the body injury caused by mercury exposure.


Assuntos
Biologia Computacional , Mercúrio/efeitos adversos , Exposição Ocupacional/efeitos adversos , Biomarcadores , Análise por Conglomerados , Perfilação da Expressão Gênica , Humanos , Fator 1 Relacionado a NF-E2/sangue , Neuroglia/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Complexo Repressor Polycomb 1/sangue , Fatores de Transcrição SOXD/sangue , Fatores de Transcrição SOXE/sangue , Transdução de Sinais
12.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070901

RESUMO

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicocálix/metabolismo , Ácido Hialurônico/metabolismo , Sindecana-1/genética , Neoplasias de Mama Triplo Negativas/genética , Via de Sinalização Wnt/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Antígeno CD24/genética , Antígeno CD24/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Bases de Dados Factuais , Feminino , Glicocálix/química , Glicocálix/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Ácido Hialurônico/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células MCF-7 , MicroRNAs/genética , MicroRNAs/metabolismo , 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 , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida , Sindecana-1/antagonistas & inibidores , Sindecana-1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
13.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188562, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964330

RESUMO

Reversible phosphorylation of proteins, controlled by kinases and phosphatases, is involved in various cellular processes. Dual-specificity phosphatases (DUSPs) can dephosphorylate phosphorylated serine, threonine and tyrosine residues. This family consists of 61 members, 44 of which have been identified in human, and these 44 members are classified into six subgroups, the phosphatase and tensin homolog (PTEN) protein phosphatases (PTENs), mitogen-activated protein kinase phosphatases (MKPs), atypical DUSPs, cell division cycle 14 (CDC14) phosphatases (CDC14s), slingshot protein phosphatases (SSHs), and phosphatases of the regenerating liver (PRLs). Growing evidence has revealed dysregulation of DUSPs as one of the common phenomenons and highlighted their key roles in human cancers. Furthermore, their differential expression may be a potential biomarker for tumor prognosis. Despite this, there are still many unstudied members of DUSPs need to further explore their precise roles and mechanism in cancers. Most importantly, the systematic review is very limited on the functional/mechanistic characteristics and clinical application of DUSPs at present. In this review, the structures, functions and underlying mechanisms of DUSPs are systematically reviewed, and the molecular and functional characteristics of DUSPs in different tumor types according to the current researches are summarized. In addition, the potential roles of the unstudied members and the possible different mechanisms of DUSPs in cancer are discussed and classified based on homology alignment and structural domain analyses. Moreover, the specific characteristics of their expression and prognosis are further determined in more than 30 types of human cancers by using the online databases. Finally, their potential application in precise diagnosis, prognosis and treatment of different types of cancers, and the main possible problems for the clinical application at present are prospected.


Assuntos
Biomarcadores Tumorais/metabolismo , Fosfatases de Especificidade Dupla/metabolismo , Neoplasias/enzimologia , Progressão da Doença , Fosfatases de Especificidade Dupla/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Neoplasias/genética , Neoplasias/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Tirosina Fosfatases/metabolismo , Transdução de Sinais
14.
Arch Biochem Biophys ; 705: 108916, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33974917

RESUMO

Noncoding RNAs (ncRNAs) have been shown to play important roles in atherosclerosis-related endothelial cells dysfunction during atherosclerosis processes. In the study, our purpose was to discover new long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) via competitively interacting each other to regulate the pathogenesis process of atherosclerosis. We investigated the roles of lncRNA AK087124 and miR-224-5p in atherosclerotic pathogenesis and found that AK087124 was up-regulated while miR-224-5p was down-regulated in in the plasma and plaque from atherosclerotic mice compared with normal mice. Ox-LDL was used to establish the mouse aorta endothelial cell (MAEC) injury model. The function study indicated that knockdown of AK087124 inhibited ox-LDL induced endothelial apoptosis and inflammatory response. Bioinformatic prediction combining with luciferase assays indicated that AK087124 could sponge miR-224-5p and enhance the PTEN expression which is a target of miR-224-5p. RNA pull down assays also showed that biotin-miR-224-5p probe could interacted directly with AK087124 and PTEN. Pearson correlation analysis further demonstrated that AK087124 and PTEN expression are negatively correlated with miR-224-5p. Rescue study revealed that miR-224-5p silencing and PTEN overexpression both can reverse the effect of AK087124 on the ox-LDL induced endothelial injury. These data indicated that AK087124 and miR-224-5p could be potential biomarkers and target molecules to treatment and diagnosis for atherosclerosis.


Assuntos
Apoptose , Aterosclerose/patologia , Células Endoteliais/patologia , MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Proliferação de Células , Camundongos , Transdução de Sinais
15.
Aging (Albany NY) ; 13(10): 14015-14038, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030133

RESUMO

BACKGROUND: Sorafenib can improve the survival of metastatic clear cell renal cell carcinoma (ccRCC) patients. However, its benefits are modest, as patients eventually become resistant, and the mechanisms remain elusive. NUPR1, a stress-induced protein, has been reported in malignancies and functions as an oncogene by modulating the stress response, facilitating survival in harsh environments and conferring drug resistance. However, its role in ccRCC has not been explored. METHODS: The expression and clinical significance of NUPR1 were analyzed in ccRCC patients in in-house patients and The Cancer Genome Atlas (TCGA) cohorts. The biological functions of NUPR1 were investigated. Xenografts were performed to confirm the effects of NUPR1 on tumorigenesis. The molecular mechanism of NUPR1 was investigated in vitro and in vivo. RESULTS: NUPR1 expression was upregulated in tumor tissue. Further analysis showed that NUPR1 overexpression was associated with an aggressive phenotype and predicted a poor prognosis. Depletion of NUPR1 suppressed tumorigenesis and sensitized cells to sorafenib treatment. Finally, mechanistic investigations indicated that NUPR1 promoted tumorigenesis in ccRCC by increasing stemness and activating the PTEN/AKT/mTOR signaling pathway. CONCLUSIONS: Collectively, our results suggest that NUPR1 may serve as a predictor of ccRCC. Notably, NUPR1 silencing reversed sorafenib resistance in ccRCC. These findings provide a novel potential therapeutic target in the clinical management of ccRCC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Sorafenibe/farmacologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Aging (Albany NY) ; 13(9): 13225-13238, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33982666

RESUMO

Melanoma is one of the most aggressive cancers with poor overall survival. To date, there are still few effective methods for the treatment of melanoma. TRIM14 was previously reported to be an important oncogene in many tumors. Nevertheless, the roles of TRIM14 in melanoma remain unknown. In this study, we found that TRIM14 was abnormally upregulated in melanoma cell lines. Knockdown of TRIM14 suppressed melanoma cell proliferation, migration, invasion, epithelial-mesenchymal transition, and melanin synthesis. Overexpression of TRIM14 had opposite effects on the cellular functions of melanoma cell lines. Further study revealed that TRIM14 knockdown increased PTEN protein levels, which in turn inactivated AKT and STAT3 pathways. Moreover, blocking AKT or STAT3 pathway with a specific inhibitor could partially reverse the promotion of melanoma malignancy mediated by TRIM14 overexpression. In addition, in vivo assay also supported the above findings. These results indicated that TRIM14 might be a promising target for melanoma treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Melanoma/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Cutâneas/genética , Proteínas com Motivo Tripartido/metabolismo , Proliferação de Células/genética , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melanoma/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/metabolismo , Proteínas com Motivo Tripartido/genética
17.
Nat Commun ; 12(1): 2550, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953176

RESUMO

Melanoma is the deadliest skin cancer. Despite improvements in the understanding of the molecular mechanisms underlying melanoma biology and in defining new curative strategies, the therapeutic needs for this disease have not yet been fulfilled. Herein, we provide evidence that the Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) contributes to melanoma development. Indeed, we show that Ambra1 deficiency confers accelerated tumor growth and decreased overall survival in Braf/Pten-mutated mouse models of melanoma. Also, we demonstrate that Ambra1 deletion promotes melanoma aggressiveness and metastasis by increasing cell motility/invasion and activating an EMT-like process. Moreover, we show that Ambra1 deficiency in melanoma impacts extracellular matrix remodeling and induces hyperactivation of the focal adhesion kinase 1 (FAK1) signaling, whose inhibition is able to reduce cell invasion and melanoma growth. Overall, our findings identify a function for AMBRA1 as tumor suppressor in melanoma, proposing FAK1 inhibition as a therapeutic strategy for AMBRA1 low-expressing melanoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Melanoma/genética , Melanoma/metabolismo , Animais , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/patologia , Camundongos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , Transcriptoma
18.
J Int Med Res ; 49(5): 3000605211014363, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34044640

RESUMO

OBJECTIVE: MicroRNAs (miRNAs) regulate prostate tumorigenesis and progression by involving different molecular pathways. In this study, we examined the role of miR-572 in prostate cancer (PCa). METHODS: The proliferation rates of LNCaP and PC-3 PCa cells were studied using MTT assays. Transwell migration and Matrigel invasion assays were performed to evaluate cell migration and invasion, respectively. Protein expression levels were examined using western blotting. Docetaxel-induced apoptosis was evaluated by Caspase-Glo3/7 assays. The putative miR-572 binding site in the phosphatase and tensin homolog (PTEN) 3' untranslated region (3' UTR) was assessed with dual-luciferase reporter assays. Additionally, miR-572 expression levels in human PCa tissues were examined by qRT-PCR assays. RESULTS: Upregulation of miR-572 promoted proliferation, migration, and invasion of PCa cells. Overexpression of miR-572 decreased sensitivity of PCa cells to docetaxel treatment by reducing docetaxel-induced apoptosis. MiR-572 can regulate migration and invasion in PCa cells. Furthermore, miR-572 could regulate expression of PTEN and p-AKT in PCa cells by directly binding to the PTEN 3' UTR. MiR-572 expression levels were increased in human PCa tissues and associated with PCa stage. CONCLUSIONS: miR-572 displayed essential roles in PCa tumor growth and its expression level may be used to predict docetaxel treatment in these tumors.


Assuntos
MicroRNAs , Neoplasias da Próstata , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética
19.
Biomolecules ; 11(4)2021 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919657

RESUMO

EPHA3, a member of the EPH family, is overexpressed in various cancers. We demonstrated previously that EPHA3 is associated with radiation resistance in head and neck cancer via the PTEN/Akt/EMT pathway; the inhibition of EPHA3 significantly enhances the efficacy of radiotherapy in vitro and in vivo. In this study, we investigated the mechanisms of PTEN regulation through EPHA3-related signaling. Increased DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2) levels, along with increased histone H3 lysine 27 trimethylation (H3K27me3) levels, correlated with decreased levels of PTEN in radioresistant head and neck cancer cells. Furthermore, PTEN is regulated in two ways: DNMT1-mediated DNA methylation, and EZH2-mediated histone methylation through EPHA3/C-myc signaling. Our results suggest that EPHA3 could display a novel regulatory mechanism for the epigenetic regulation of PTEN in radioresistant head and neck cancer cells.


Assuntos
Repressão Epigenética , Neoplasias de Cabeça e Pescoço/genética , PTEN Fosfo-Hidrolase/genética , Tolerância a Radiação , Receptor EphA3/genética , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Código das Histonas , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Receptor EphA3/metabolismo
20.
Aging (Albany NY) ; 13(7): 10015-10033, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33795530

RESUMO

Ameliorating hyperglycemia and insulin resistance are major therapeutic strategies for type 2 diabetes. Previous studies have indicated that photobiomodulation therapy (PBMT) attenuates metabolic abnormalities in insulin-resistant adipose cells and tissues. However, it remains unclear whether PBMT ameliorates glucose metabolism in skeletal muscle in type 2 diabetes models. Here we showed that PBMT reduced blood glucose and insulin resistance, and reversed metabolic abnormalities in skeletal muscle in two diabetic mouse models. PBMT accelerated adenosine triphosphate (ATP) and reactive oxygen species (ROS) generation by elevating cytochrome c oxidase (CcO) activity. ROS-induced activation of phosphatase and tensin homolog (PTEN)/ protein kinase B (AKT) signaling after PBMT promoted glucose transporter GLUT4 translocation and glycogen synthase (GS) activation, accelerating glucose uptake and glycogen synthesis in skeletal muscle. CcO subunit III deficiency, ROS elimination, and AKT inhibition suppressed the PBMT effects of glucose metabolism in skeletal muscle. This study indicated amelioration of glucose metabolism after PBMT in diabetic mouse models and revealed the metabolic regulatory effects and mechanisms of PBMT on skeletal muscle.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hiperglicemia/terapia , Resistência à Insulina/fisiologia , Terapia com Luz de Baixa Intensidade , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Hiperglicemia/metabolismo , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...