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2.
Expert Opin Ther Pat ; 29(11): 881-889, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530116

RESUMO

Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued. Areas covered: Here the authors provide recent updates to their previous publication on 'PTEN modulators: A patent review', and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson's disease, Alzheimer's disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn's disease, and several cancer types. Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.


Assuntos
Desenvolvimento de Medicamentos/métodos , PTEN Fosfo-Hidrolase/efeitos dos fármacos , Animais , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Patentes como Assunto , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
3.
Oncol Rep ; 42(4): 1580-1588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364747

RESUMO

The objectives of the present study were to obtain the multigene mutation spectra of female breast cancer patients in Northeast China, to explore the correlation between mutations and clinicopathological characteristics, and to identify genetic mutations that correlate with the prognosis and survival of breast cancer patients. An Ion Torrent sequencing platform was used to detect mutations, including 31 known gene mutations associated with breast cancer, in 621 specimens from 286 breast cancer patients. A total of 286 patients were enrolled in this study. Eleven harmful/pathogenic gene mutations were found in 54.2% (155/286) of the patients, and 179 somatic nonsynonymous mutations were detected. Approximately 5.6% (16/286) of the patients carried two or more gene mutations. Among the 11 pathogenic gene mutations, those in PIK3CA were the most common and were detected in 65.4% (117/179) of the patients; TP53 gene mutations were the second most common and were detected in 20.7% (37/179) of the patients. Additional mutations were found in AKT (14/179; 7.8%) and PTEN (4/179; 2.2%), and mutations in the remaining 7 genes were each detected in approximately 0.6% (1/179) of the patients. Excluding 6 cases of breast ductal carcinoma in situ, the remaining 280 breast cancer cases were divided into four groups by molecular subtype, and the mutation frequencies of the 11 breast cancer­associated genes differed among the four groups. Furthermore, these 280 breast cancer cases were divided into two clinically relevant therapeutic groups: the HR+/HER2­ and triple­negative groups. The triple­negative group had a high frequency of TP53 mutations (21.8%) and a low frequency of PIK3CA mutations (21.8%), whereas the HR+/HER2­ group harbored TP53 mutations at a low frequency (10.1%) and PIK3CA mutations at a high frequency (50.0%). Cancerous, paracancerous, and normal tissues were collected from 72 patients and subjected to next­generation sequencing. The types and frequencies of somatic nonsynonymous mutations differed among the three studied tissue types, reflecting the genetic heterogeneity of different tissues from the same individual. In addition, tissues from 70 patients (excluding 2 patients with ductal carcinoma in situ) were divided into four groups according to molecular subtype, and the gene mutation frequencies in cancerous, paracancerous, and normal tissues differed among the four groups. After normalization, gene mutations were detected at a higher rate in cancerous tissues than in paracancerous and normal tissues in all groups, except for the HER2­positive group (which had a small sample size). In addition, Cox multivariate analyses of clinicopathological data, gene sequencing results, and 5­year survival rates of the 286 patients showed that gene mutations in the PTEN­PI3K/AKT signaling pathway were independently associated with a poor prognosis (P<0.05). In conclusion, mutations in the PTEN­PI3K/AKT signaling pathway may be valuable in the prediction of the prognosis and survival of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Família Multigênica , Mutação , Adulto , Neoplasias da Mama/enzimologia , China , Análise Mutacional de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Lesões Pré-Cancerosas/enzimologia , Lesões Pré-Cancerosas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
4.
Adv Exp Med Biol ; 1155: 533-541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468429

RESUMO

Taurine displays anti-tumor activity in some kinds of human cancers. However, the underlying mechanisms are poorly understood. Epstein-Barr virus-related nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer in Southeast Asia with the highest incidence in South China. We examined an apoptosis-inducing effect of taurine against NPC cells (HK1 and HK1-EBV) to clarify the mechanisms of anti-tumor effects of taurine by immunocytochemical methods. We observed that taurine induced cleavage of caspase-9/3 in a concentration-dependent manner, suggesting the involvement of mitochondrial apoptotic signals. Both PTEN and p53 activation were detected in a dose-dependent manner after taurine treatment in NPC cells. In conclusion, taurine may play an anti-tumor role by activating tumor suppressor PTEN and p53.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Taurina/farmacologia , Linhagem Celular Tumoral , China , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
5.
Life Sci ; 232: 116656, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306658

RESUMO

AIMS: Tamoxifen-induced liver-specific Dicer1 deletion (iDicer1-/-) in mature mice may provide clues demonstrating the genuine effects of acute loss of Dicer1 and miRNAs in the liver regeneration process. MAIN METHODS: In this study, mice with tamoxifen-induced Dicer1 deletion through the Cre/LoxP system were constructed and then underwent classic 70% partial hepatectomy or CCl4-induced liver injury. To rescue the inhibitory effect of Dicer1 ablation on liver regeneration, miR-21 agomir was injected into the tail vein of iDicer1-/- mice. KEY FINDINGS: Unlike constitutive embryonic deletion of Dicer1, tamoxifen-induced Dicer1 deletion did not result in severe liver injury or lesions, providing an ideal model for investigating acute loss of Dicer1 and miRNAs in liver regeneration. Dicer1 deletion led to impaired liver regeneration through the inhibitory effect of miR-21 on PTEN and Rhob expression. SIGNIFICANCE: In our previous study, we found that embryonic loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation, while the role of Dicer1 in liver regeneration remains largely unknown. We clearly identified the promotion effect of Dicer1 on liver regeneration by increasing miR-21 expression, which inhibits the expression of two negative cell proliferation regulators, Pten and Rhob.


Assuntos
RNA Helicases DEAD-box/fisiologia , Regeneração Hepática/fisiologia , MicroRNAs/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Ribonuclease III/fisiologia , Proteína rhoB de Ligação ao GTP/metabolismo , Animais , RNA Helicases DEAD-box/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Camundongos Knockout , Ribonuclease III/genética , Tamoxifeno/administração & dosagem
6.
Life Sci ; 232: 116613, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265853

RESUMO

AIMS: Sepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy. MAIN METHODS: A sepsis model was established via the cecum ligation and puncture of male Sprague-Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR. KEY FINDINGS: VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats. SIGNIFICANCE: This study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD.


Assuntos
PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Ácido Valproico/farmacologia , Disfunção Ventricular/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Ceco/metabolismo , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Disfunção Ventricular/microbiologia , Disfunção Ventricular/patologia
7.
BMC Bioinformatics ; 20(1): 385, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288758

RESUMO

BACKGROUND: In cancer research, robustness of a complex biochemical network is one of the most relevant properties to investigate for the development of novel targeted therapies. In cancer systems biology, biological networks are typically modeled through Ordinary Differential Equation (ODE) models. Hence, robustness analysis consists in quantifying how much the temporal behavior of a specific node is influenced by the perturbation of model parameters. The Conditional Robustness Algorithm (CRA) is a valuable methodology to perform robustness analysis on a selected output variable, representative of the proliferation activity of cancer disease. RESULTS: Here we introduce our new freely downloadable software, the CRA Toolbox. The CRA Toolbox is an Object-Oriented MATLAB package which implements the features of CRA for ODE models. It offers the users the ability to import a mathematical model in Systems Biology Markup Language (SBML), to perturb the model parameter space and to choose the reference node for the robustness analysis. The CRA Toolbox allows the users to visualize and save all the generated results through a user-friendly Graphical User Interface (GUI). The CRA Toolbox has a modular and flexible architecture since it is designed according to some engineering design patterns. This tool has been successfully applied in three nonlinear ODE models: the Prostate-specific Pten-/- mouse model, the Pulse Generator Network and the EGFR-IGF1R pathway. CONCLUSIONS: The CRA Toolbox for MATLAB is an open-source tool implementing the CRA to perform conditional robustness analysis. With its unique set of functions, the CRA Toolbox is a remarkable software for the topological study of biological networks. The source and example code and the corresponding documentation are freely available at the web site: http://gitlab.ict4life.com/SysBiOThe/CRA-Matlab .


Assuntos
Algoritmos , Modelos Biológicos , Neoplasias/metabolismo , Software , Biologia de Sistemas/métodos , Animais , Simulação por Computador , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Humanos , Cinética , Masculino , Camundongos , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Próstata/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
8.
Braz J Med Biol Res ; 52(7): e8381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241714

RESUMO

Experiments were conducted to determine if the follicle-stimulating hormone (FSH) receptor binding inhibitor (FRBI) impacts the expression levels of AT-rich interactive domain-containing protein 1A (ARID1A) and phosphatase and tensin homolog (PTEN) in ovaries and blood, as well as expressions of follicle-stimulating hormone cognate receptor (FSHR) gene and proteins. Mice in FRBI-10, FRBI-20, FRBI-30, and FRBI-40 groups were intramuscularly injected with 10, 20, 30, and 40 mg FRBI/kg, respectively, for five consecutive days. Western blotting and qRT-PCR were utilized to determine expression levels of ARID1A and PTEN proteins and mRNAs. Serum ARID1A and PTEN concentrations of the FRBI-40 group were higher than the control group (CG) and FSH group (P<0.05). FSHR mRNA levels of FRBI-20, FRBI-30, and FRBI-40 groups were lower than that of CG and FSH groups on day 15 (P<0.05 or P<0.01). Expression levels of FSHR proteins of FRBI-30 and FRBI-40 groups were lower than those of CG and FSH groups (P<0.05). Levels of ARID1A and PTEN proteins of the FRBI-30 group were greater than CG on days 20 and 30 (P<0.05). FRBI doses had significant positive correlations to levels of ARID1A and PTEN proteins. Additionally, ARID1A and PTEN had negative correlations to FSHR mRNAs and proteins. A high dose of FRBI could promote the expression levels of ARID1A and PTEN proteins in ovarian tissues. FRBI increased serum concentrations of ARID1A and PTEN. However, FRBI depressed expression levels of FSHR mRNAs and proteins in mouse ovaries.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Hormônio Foliculoestimulante/metabolismo , Proteínas Nucleares/sangue , Neoplasias Ovarianas/metabolismo , PTEN Fosfo-Hidrolase/sangue , Receptores do FSH/antagonistas & inibidores , Animais , Western Blotting , Proteínas de Ligação a DNA/sangue , Feminino , Camundongos , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Ativação Transcricional/genética , Regulação para Cima
9.
Oncology ; 97(3): 164-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195398

RESUMO

BACKGROUND: MicroRNAs are a class of small noncoding RNAs that play an important role in progression and drug resistance in cancer. Several reports have shown that miR-130b modulates cell growth and drug resistance in some cancers. However, the expression and biological role of miR-130b in renal cell carcinoma (RCC) remain poorly understood. This study aimed to examine the expression and functional role of miR-130b and to analyze the association between miR-130b and sunitinib resistance in RCC. METHODS: The expression of miR-130b in 32 RCC tissues and their corresponding normal kidney tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We performed a 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay in RCC cell lines transfected with miR-130b inhibitor or miR-130b mimics. We evaluated the relationship between miR-130b and PTEN and also analyzed the effect of miR-130b on sunitinib resistance. RESULTS: qRT-PCR analysis showed that the expression of miR-130b was higher in RCC tissues than in corresponding normal kidney tissues. The MTT assay revealed that miR-130b modulated cell growth. qRT-PCR revealed an inverse correlation between miR-130b and PTEN in RCC. Western blotting demonstrated that miR-130b regulated the expression of PTEN in the RCC cell line. Additionally, miR-130b was associated with sunitinib resistance through regulation of PTEN. We established the sunitinib-resistant Caki-1 (Caki-1-SR) cells and observed that the expression of miR-130b was elevated in Caki-1-SR cells compared with parental Caki-1 cells. Knockdown of miR-130b improved sunitinib resistance in Caki-1-SR cells. CONCLUSION: The expression of miR-130b was upregulated in RCC. miR-130b promoted cell growth and was associated with sunitinib resistance through regulating PTEN expression. Collectively, these results suggest that miR-130b may play an oncogenic role and be a promising therapeutic target.


Assuntos
Carcinoma de Células Renais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Sunitinibe/farmacologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Técnicas de Inativação de Genes , Humanos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , PTEN Fosfo-Hidrolase/metabolismo
10.
Gene ; 710: 103-113, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158447

RESUMO

Epithelial-mesenchymal transition (EMT) symbolizes the predominant program of advanced-stage cancer, it is critical in cancer progression, metastasis, and chemotherapy resistance. In this study, the metastatic properties of nasopharyngeal carcinoma (NPC) cells were evaluated by morphological examination, wound healing assay, migration and invasion assay. Western blotting and qRT-PCR were used to ascertain the expression of markers which were associated with EMT. The effects of miR-205-5p on invasion, migration, EMT and proliferation of NPC cells were evaluated and the molecular mechanisms of their interaction were explored. In this study, we manifested firstly that the expression of miR-205-5p in cisplatin-resistant NPC cell line HNE1/DDP was obviously up-regulated than that in its parental cell line HNE1. Then we analyzed the specific role of miR-205-5p through functional assays by transfecting specific mimics and inhibitors. The results indicated that low expression of miR-205-5p restrained EMT progression of HNE1/DDP cells. Further studies on the mechanism of miR-205-5p manifested that PTEN was a downstream candidate gene of miR-205-5p, down-regulated PTEN expression could counteract the effect of miR-205-5p inhibitors, and the regulation of EMT by miR-205-5p on HNE1/DDP cells depended on the PI3K/AKT signaling pathway. Overall, our results indicated that miR-205-5p was targeting PTEN to regulate EMT through the PI3K/AKT pathway. This study will supply a new treatment target for advanced NPC.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , PTEN Fosfo-Hidrolase/genética , Regulação para Cima , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Food Chem Toxicol ; 131: 110552, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163220

RESUMO

[OBJECTIVE]: Di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, may act as an endocrine disruptor and cause developmental toxicity. Differentiated human embryonic stem cells (hESCs) were used to investigate the underlying mechanism of the embryotoxicity induced by DEHP. [Materials and Methods] H9-hESCs were treated with DEHP at different concentrations for 10 days, and the cytotoxicity of DEHP on cell proliferation was determined using a cell-microelectronic sensing technique (Real-Time Cellular Analysis: RTCA). Based on the 50% inhibitory proliferation concentration (IC50), differentiated H9-hESCs were treated with DEHP at 0, 50, 100, and 200 µg/ml for 120 h, followed by measurement of its toxic effects on the transcriptome by mRNA microarray and QuantiGene Plex (QGP). Proteins were detected by the iTRAQ-based proteomics method and the proteins related to the PPARγ/PTEN/Akt pathways were measured by western blotting. The progression of the cell cycle and apoptosis were characterized using flow cytometry (FCM). In other experiments, hESCs were pre-treated with GW9662 (20 µM), a specific PPARγ inhibitor, for 30 min, followed by exposure to GW9662 (20 µM) and DEHP (200 µg/ml) for 120 h to observe the underlying mechanism of DEHP's embryotoxicity. [RESULTS]: DEHP inhibited H9-hESC cell proliferation in a dose-dependent manner, with an IC50 of 165.78 µg/ml. FCM results showed that DEHP could markedly induce cell cycle arrest and increase apoptosis. Gene microarray and QPG array analyses indicated that the peroxisome proliferator-activated receptor γ (PPARγ) was an apparent target for DEHP. We further demonstrated that DEHP could activate the PPARγ and upregulate the expression of PTEN downstream genes, and then play a negative role in the AKT signaling pathway. Cells pretreated with PPARγ inhibitor, GW9662, were shown to restore the effect of DEHP on the PPARγ/PTEN/AKT signaling pathway, and induce the recovery of cell cycle arrest and apoptosis. [CONCLUSION]: DEHP inhibited cell proliferation, promoted cell cycle arrest, and induced apoptosis through the PPARγ/PTEN/AKT signaling pathway in differentiated human embryonic stem cells. It suggested that DEHP exposure possibly cause reproductive or developmental toxicity in humans through the PPARγ signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Emulsões/síntese química , Emulsões/química , Humanos , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Plastificantes/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Soroalbumina Bovina/química , Teratogênios/toxicidade
12.
J Cancer Res Clin Oncol ; 145(7): 1681-1693, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31175464

RESUMO

OBJECTIVE: To study integrin α6 expression in lung adenocarcinoma tissue through comparison with matching adjacent non-cancerous tissues as well as elucidating the correlation between integrin α6 expression with the clinical parameters of lung adenocarcinoma. We also explore the signal pathways associated with integrin α6 up-regulation. METHODS: The clinical data, cancer tissues, and adjacent non-cancerous tissues of 30 patients diagnosed with lung adenocarcinoma were collected from Taizhou Hospital in Zhejiang Province, China, in 2010. The protein levels of integrin α6 were determined by immunohistochemistry methods. mRNA data of 85 lung adenocarcinoma tissues and 14 normal tissues as well as clinical results were collected from GEO30219. We also collected mRNA data of 533 lung adenocarcinoma tissues and 59 normal tissues as well as the clinical results of 522 patients with lung adenocarcinoma from the Cancer Genome Atlas (TCGA) database. The differences in protein and mRNA levels in cancer tissues and non-cancerous tissues were analyzed, and we subsequently investigated the association between integrin α6 expression and key parameters indicating lung adenocarcinoma progression and overall survival rate. Additionally, the possible pathways involved in the up-regulation of integrin α6 were analyzed by GSEA. RESULTS: The protein levels of integrin α6 in lung adenocarcinoma tissues were significantly higher than those in adjacent tissues (p < 0.01), and were positively correlated with the grade and T stage of lung adenocarcinoma (p < 0.05). Patients with low integrin α6 protein levels had higher survival rates (p < 0.05). The analysis of gene chip data from the TCGA database also showed that the integrin α6 mRNA level was significantly correlated with T stage (p < 0.05), overall survival (OS) rate (p < 0.01), and disease-free survival (DFS) rate (p = 0.005). GSEA gene enrichment analysis identified a series of pathways that may be associated with integrin α6 up-regulation, including the AGR, PYK2, ECM, and PTEN pathways. CONCLUSION: Integrin α6 plays an important role in the occurrence and progression of lung adenocarcinoma and may act as a prognostic predictor of lung adenocarcinoma in patients. Based on the results of the present study, integrin α6 may be a potential target gene for the treatment of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Integrina alfa6/biossíntese , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biologia Computacional , Humanos , Imuno-Histoquímica , Integrina alfa6/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Análise Serial de Tecidos , Regulação para Cima
13.
Mol Med Rep ; 19(6): 5345-5352, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059054

RESUMO

Myofibroblast transdifferentiation is an important feature of cardiac fibrosis. Previous studies have indicated that microRNA­216a (miR­216a) is upregulated in response to transforming growth factor­ß (TGF­ß) in kidney cells and can activate Smad3; however, its role in myofibroblast transdifferentiation remains unclear. The present study aimed to investigate the role of miR­216a in TGF­ß­induced myofibroblast transdifferentiation, and to determine the underlying mechanisms. Adult mouse cardiac fibroblasts were treated with TGF­ß to induce myofibroblast transdifferentiation. An antagomir and agomir of miR­216a were used to inhibit or overexpress miR­216a in cardiac fibroblasts, respectively. Myofibroblast transdifferentiation was evaluated based on the levels of fibrotic markers and α­smooth muscle actin expression. The miR­216a antagomir attenuated, whereas the miR­216a agomir promoted TGF­ß­induced myofibroblast transdifferentiation. Mechanistically, miR­216a accelerated myofibroblast transdifferentiation via the AKT/glycogen synthase kinase 3ß signaling pathway, independent of the canonical Smad3 pathway. In addition, it was observed that miR­216a activated AKT via the downregulation of PTEN. In conclusion, miR­216a was involved in the regulation of TGF­ß­induced myofibroblast transdifferentiation, suggesting that targeting miR­216a may aid in developing effective interventions for the treatment of cardiac fibrosis.


Assuntos
Transdiferenciação Celular/efeitos dos fármacos , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Miofibroblastos/citologia , Miofibroblastos/metabolismo , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Smad3/metabolismo
14.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035650

RESUMO

Citrate is a key intermediate of the tricarboxylic acid cycle and acts as an allosteric signal to regulate the production of cellular ATP. An elevated cytosolic citrate concentration inhibits growth in several types of human cancer cells; however, the underlying mechanism by which citrate induces the growth arrest of cancer cells remains unclear. The results of this study showed that treatment of human pharyngeal squamous carcinoma (PSC) cells with a growth-suppressive concentration of citrate caused cell cycle arrest at the G2/M phase. A coimmunoprecipitation study demonstrated that citrate-induced cell cycle arrest in the G2/M phase was associated with stabilizing the formation of cyclin B1-phospho (p)-cyclin-dependent kinase 1 (CDK1) (Thr 161) complexes. The citrate-induced increased levels of cyclin B1 and G2/M phase arrest were suppressed by the caspase-3 inhibitor Ac-DEVD-CMK and caspase-3 cleavage of mutant p21 (D112N). Ectopic expression of the constitutively active form of protein kinase B (Akt1) could overcome the induction of p21 cleavage, cyclin B1-p-CDK1 (Thr 161) complexes, and G2/M phase arrest by citrate. p85α-phosphatase and tensin homolog deleted from chromosome 10 (PTEN) complex-mediated inactivation of Akt was required for citrate-induced G2/M phase cell cycle arrest because PTEN short hairpin RNA or a PTEN inhibitor (SF1670) blocked the suppression of Akt Ser 473 phosphorylation and the induction of cyclin B1-p-CDK1 (Thr 161) complexes and G2/M phase arrest by citrate. In conclusion, citrate induces G2/M phase arrest in PSC cells by inducing the formation of p85α-PTEN complexes to attenuate Akt-mediated signaling, thereby causing the formation of cyclin B1-p-CDK1 (Thr 161) complexes.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácido Cítrico/farmacologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Faríngeas/metabolismo , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Ciclina B1/metabolismo , Humanos , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Neoplasias Faríngeas/genética , Fosforilação , Transdução de Sinais
15.
Yonsei Med J ; 60(6): 561-569, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31124340

RESUMO

PURPOSE: Liver fibrosis is a major cause of morbidity and mortality and the outcome of various chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrosis. Studies have confirmed that miR-140-3p plays a potential regulatory effect on HSC activation. However, whether miR-140-3p mediates the liver fibrosis remains unknown. MATERIALS AND METHODS: Expression of miR-140-3p was detected by real-time quantitative PCR (qPCR). Cell proliferation was measured by MTT, while cell apoptosis rate was determined via flow cytometry. Western blot assay was used to detect the expression of cleaved PARP. The fibrogenic effect was evaluated by expression of α-smooth muscle actin and desmin. Functional experiments were performed in transforming growth factor ß1 (TGF-ß1)-induced HSC-T6 cells with transfection of anti-miR-140-3p and/or siPTEN. Target binding between miR-140-3p and PTEN was predicted by the TargetScan database and identified using luciferase reporter assay and RNA immunoprecipitation. RESULTS: TGF-ß1 induced the activation of HSC-T6 cells, and miR-140-3p expression varied according to HSC-T6 cell activation status. Knockdown of miR-140-3p reduced cell proliferation and the expressions of α-SMA and desmin, as well as increased apoptosis, in TGF-ß1-induced HSC-T6 cells, which could be blocked by PTEN silencing. Additionally, inactivation of the AKT/mTOR signaling pathway stimulated by miR-140-3p knockdown was abolished when silencing PTEN expression. PTEN was negatively regulated by miR-140-3p via direct binding in HSC-T6 cells. CONCLUSION: miR-140-3p is an important mediator in HSC-T6 cell activation, and miR-140-3p knockdown suppresses cell proliferation and fibrogenesis in TGF-ß1-induced HSC-T6 cells, indicating that miR-140-3p may be a potential novel molecular target for liver fibrosis.


Assuntos
Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/patologia , Cirrose Hepática/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular , Proliferação de Células/genética , Regulação da Expressão Gênica , Inativação Gênica , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/patologia , MicroRNAs/genética , Transdução de Sinais/efeitos dos fármacos
16.
Biol Res ; 52(1): 26, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053167

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive and mostly incurable hematological malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcomes. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show biological anti-tumor characteristics in our previous studies. However, its potential effect on leukemia remains unknown. The present research aims to investigate the underlying mechanism of treating leukemia with ATPR in vitro. METHODS: In this study, the AML cell lines NB4 and THP-1 were treated with ATPR. Cell proliferation was analyzed by the CCK-8 assay. Flow cytometry was used to measure the cell cycle distribution and cell differentiation. The expression levels of cell cycle and differentiation-related proteins were detected by western blotting and immunofluorescence staining. The NBT reduction assay was used to detect cell differentiation. RESULTS: ATPR inhibited cell proliferation, induced cell differentiation and arrested the cell cycle at the G0/G1 phase. Moreover, ATPR treatment induced a time-dependent release of reactive oxygen species (ROS). Additionally, the PTEN/PI3K/Akt pathway was downregulated 24 h after ATPR treatment, which might account for the anti-AML effects of ATPR that result from the ROS-mediated regulation of the PTEN/PI3K/AKT signaling pathway. CONCLUSIONS: Our observations could help to develop new drugs targeting the ROS/PTEN/PI3K/Akt pathway for the treatment of AML.


Assuntos
Antineoplásicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Retinoides/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Fluorimunoensaio , Humanos , Leucemia Mieloide Aguda , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
17.
J Cancer Res Clin Oncol ; 145(7): 1751-1759, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129769

RESUMO

BACKGROUND: Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease. DESIGN: 228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort. RESULTS: TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15-16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67-3.18, p < 0.0001) and (HR 3.99, CI: 2.43-6.56; p < 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49-3.62; p < 0.0001) and PCSM (HR = 3.44, CI: 1.75-6.78, p < 0.0001). CONCLUSION: The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease.


Assuntos
PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/metabolismo , Fator Trefoil-3/metabolismo , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/metabolismo , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , PTEN Fosfo-Hidrolase/deficiência , Prostatectomia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Análise Serial de Tecidos , Fator Trefoil-3/deficiência
18.
Life Sci ; 230: 28-34, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31108094

RESUMO

Psoriasis, a chronic inflammatory skin disorder disease, is closely associated with hyperproliferation of keratinocytes. Upregulated miR-223 has been found in peripheral blood mononuclear cells from patients with psoriasis and from psoriatic skin. However, its role in keratinocytes remains unknown. We thus aimed to investigate the function of miR-223 in psoriasis. Interleukin-22 (IL-22) is a crucial keratinocyte trigger in the T-cell-mediated immune response to psoriasis. We found miR-223 to be overexpressed in psoriatic lesions and in IL-22-stimulated HaCaT cells. HaCaT cells then were transfected with a miR-223 mimic or inhibitor to overexpress or inhibit expression of miR-223, respectively. A Cell Counting Kit-8 assay revealed that miR-223 overexpression promoted and miR-223 downregulation inhibited proliferation in IL-22-stimulated HaCaT cells. Flow cytometry analysis certified that miR-223 overexpression decreased HaCaT cell apoptosis, whereas miR-223 downregulation increased it. A dual-luciferase reporter assay demonstrated that miR-223 directly targeted the phosphatase and tensin homolog (PTEN) gene. MiR-223 also negatively regulated mRNA and protein expression of PTEN and modulated the PTEN/Akt pathway in IL-22-stimulated HaCaT cells. PTEN silencing attenuated the activity of the miR-223 inhibitor in these cells via the PTEN/Akt pathway. Overall, the results showed that miR-223 increased proliferation and inhibited apoptosis of IL-22-stimulated keratinocytes via the PTEN/Akt pathway.


Assuntos
Queratinócitos/fisiologia , MicroRNAs/fisiologia , Psoríase/genética , Apoptose/genética , Linhagem Celular , Proliferação de Células/genética , Humanos , Interleucinas/genética , Interleucinas/imunologia , Queratinócitos/metabolismo , Leucócitos Mononucleares/metabolismo , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
19.
Life Sci ; 230: 162-168, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125562

RESUMO

AIMS: Jumonji AT-rich interactive domain 2 (Jarid2) is an interacting component of PRC2 which catalyzes methylation of H3K27 (H3K27me3) and causes the downregulation of PTEN. In the present study, we aimed to explore whether Jarid2 could interact with H3K27me3 to regulate PTEN expression in bladder cancer. MAIN METHODS: Jarid2 expression in bladder cancer tissues and cells were determined by western blotting and RT-PCR. CCK-8, flow cytometry, transwell chamber and in vivo xenograft assays were performed to assess cell growth, apoptosis, migration and tumorigenesis, respectively. Chromatin immunoprecipitation (ChIP) assay was used to assess the methylation of PTEN. KEY FINDINGS: Jarid2 expression was increased in bladder cancer tissues and cells. Downregulation of Jarid2 with shRNA transfection obviously inhibited the proliferation, migration and tumorigenesis of bladder cancer T24 and HT-1376 cells and induced cell apoptosis. Jarid2 downregulation decreased the expression of p-AKT and increased PTEN expression. Besides, Jarid2 down-regulation repressed the epithelial-mesenchymal transition (EMT), whereas knockdown of PTEN impaired this effect. Moreover, upregulation of Jarid2 increased the combination of PTEN promoter and H3K27me3, and 5-aza-CdR rescued it. Meanwhile, 5-aza-CdR administration abolished Jarid2 roles in the promotion of EMT process and AKT activation, as well as the reduction of PTEN expression. SIGNIFICANCE: Overall, the present study elaborated that Jarid2 facilitated the progression of bladder cancer through H3K27me3-mediated PTEN downregulation and AKT activation, which might provide a new mechanism for Jarid2 in promoting bladder cancer progression.


Assuntos
Complexo Repressor Polycomb 2/fisiologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/genética , China , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Histonas/efeitos dos fármacos , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
Nat Commun ; 10(1): 2226, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110221

RESUMO

Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.


Assuntos
Carcinogênese/genética , Polpa Dentária/citologia , Células-Tronco Mesenquimais/patologia , Osteogênese/genética , PTEN Fosfo-Hidrolase/metabolismo , Adipócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Carcinogênese/patologia , Diferenciação Celular/genética , Células Cultivadas , Criança , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Polpa Dentária/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/metabolismo , Código das Histonas/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética , Análise de Sequência de RNA
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