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1.
Life Sci ; 232: 116614, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260682

RESUMO

AIMS: SRY-box 18 (SOX18) is a transcription factor known for its role in regulating cell differentiation and lymphatic and blood vessel development. It has been reported that SOX18 was involved in various diseases, including cancer. This study aimed to explore the significance and biological function of SOX18 in bladder cancer (BCa). MATERIALS AND METHODS: SOX18 expression in BCa and normal tissues was analyzed by immunohistochemistry, and SOX18 expression in BCa cell lines was quantified by western blotting and quantitative real-time PCR. The role of SOX18 on the proliferation, migration and invasion of BCa cells was explored by CCK-8 and transwell invasion assays in vitro. Cell cycle was measured by flow cytometry assays. Western blotting and qRT-PCR were performed to investigate the potential mechanisms by which SOX18 leads to tumor progression. KEY FINDINGS: SOX18 was significantly upregulated in BCa and its expression was associated with clinical features of patients with BCa. Our data demonstrated that SOX18 promoted cell proliferation via accelerating cell cycle and by regulating c-Myc and Cyclin D1, promoted cell invasion via upregulation of MMP-7. Moreover, phosphorylation of c-Met and Akt regulated by SOX18 was identified to be involved in the process of cell migration and invasion, indicating the vital role of SOX18 in the metastasis of BCa. SIGNIFICANCE: Our data demonstrated a cancer-promoting effect of SOX18 in BCa, revealed the potential mechanisms of SOX18 in mediating cellular functions, and indicated that SOX18 may serve as a promising progression and prognostic biomarker and a therapeutic target for BCa.


Assuntos
Fatores de Transcrição SOXF/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Ciclina D1/metabolismo , Feminino , Fase G1/fisiologia , Xenoenxertos , Humanos , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fase S/fisiologia , Fatores de Transcrição SOXF/biossíntese , Fatores de Transcrição SOXF/genética , Transcriptoma/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
2.
Environ Pollut ; 252(Pt A): 216-226, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31151060

RESUMO

Microcystins (MCs) have been shown to be carcinogenic by animal and cellular experiments and found to be associated with the development of human hepatocellular carcinoma (HCC) through epidemiological studies. However, the molecular mechanism of microcystin-LR (MC-LR) induced HCC is still unclear. This study is determined to clarify the role and mechanism of LHX6 in MC-LR-induced hepatocarcinogenesis. Using the previously established MC-LR-induced malignant transformation model in L02 cells, we screened out LHX6, homeobox gene that was significantly changed. We found that LHX6 was significantly down-regulated in MC-LR treated L02 cells and the liver tissue of rats treated for 35 weeks with 10 µg/kg body weight of MC-LR. Expression of LHX6 in human tumor tissue was significantly down-regulated in high MC-LR-exposure group. LHX6 was hypermethylated in MC-LR treated L02 cells and up-regulated after treatment with 10 µM of 5-aza-2'-deoxycytidine. Furthermore, overexpression of LHX6 inhibited proliferation, invasion and migration of malignantly transformed L02 cells in vitro and in vivo, while knockdown of LHX6 resulted in an opposite phenotype. In addition, we found that up-regulation of P53 and Bax resulted in apoptosis, and that down-regulation of CTNNB1 and MMP7 led to migration of MC-LR treated L02 cells. Blockade of P53 and CTNNB1 by its inhibitor significantly diminished the effect of LHX6. These genes were working together during the process of MC-LR-induced hepatocarcinogenesis. Our study demonstrated for the first time that LHX6 gene expression is regulated by DNA methylation and can inhibit the proliferation, invasion and migration through Wnt/ß-catenin and P53 signaling pathways during the MC-LR-induced hepatocarcinogenesis. This result may suggest that LHX6 gene can be used as a potential target gene and a biomarker for liver cancer treatment.


Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Transformação Celular Neoplásica/induzido quimicamente , Proteínas com Homeodomínio LIM/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Microcistinas/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Epigênese Genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metaloproteinase 7 da Matriz/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Transdução de Sinais , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
3.
Theriogenology ; 131: 123-132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959438

RESUMO

This study was designed to examine changes in target transcript abundance in endometrial explants exposed to pregnancy-associated glycoproteins (PAGs). Endometrial explants from pregnant and non-pregnant heifers collected on day18 (day 0: day of insemination) were incubated in the absence or presence of PAGs (15 µg/ml). The PAGs represented a mixture comprised of approximately equal amounts of bovine PAGs 4, 6, and 9. Samples were harvested for RNA extraction after 24 h or 96 h of incubation. Transcript abundance for target genes related to prostaglandin synthesis (PTGES), a chemokine (CXCL5) and tissue remodeling (EMMPRIN; MMPs 1, 2, 3, 7, 8, and 9; PLAU; SPP1; TIMP1 and TIMP2) were analyzed by quantitative PCR. Changes in relative transcript abundance for MMP1, MMP3, MMP7, PLAU, EMMPRIN and SPP1 were observed after PAG exposure in both non-pregnant and pregnant endometrium (P < 0.05). However, some of the transcripts associated with tissue remodeling were altered only at certain time points (either 24 h or 96 h). The transcript for bovine CXCL5 was increased in non-pregnant endometrium four- and six-fold at 24 h and 96 h of PAG exposure, respectively (P < 0.05); in pregnant endometrium, only the 24 h incubation period exhibited an elevation in CXCL5 (P < 0.05). In non-pregnant endometrium, both PTGES and MMP9 were elevated after exposure to PAGs for 24 h (P < 0.05) but not in the other samples. Some interferon-responsive transcripts (IFI6, ISG15) were found to be more abundant (P < 0.05) in pregnant endometrium after 96 h exposure to PAGs compared to endometrium that had not been exposed to the PAGs. Likewise, ISG15 message was elevated (P = 0.06) in non-pregnant endometrium after 24 h incubation with PAGs. These results indicate that the PAGs used in this experiment were able to induce changes in endometrial transcripts encoding for proteins associated with matrix remodeling as well as chemokine production and prostaglandin release.


Assuntos
Bovinos , Endométrio/metabolismo , Glicoproteínas/farmacologia , Animais , Basigina/genética , Basigina/metabolismo , Feminino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Gravidez , RNA Mensageiro/metabolismo
4.
J Physiol Biochem ; 75(2): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972697

RESUMO

Altered glycosylation is a common feature of cancer cells and plays an important role in tumor progression. ß-Galactoside α2-6-sialyltransferase 1 (ST6Gal-I) is the critical sialyltransferase responsible for the addition of α2-6-sialic acid to the terminal N-glycans on the cell surface. However, the functions and mechanism of ST6Gal-I in tumor immune escape remain poorly understood. Here, we found that ST6Gal-I overexpression promoted hepatocarcinoma cell proliferation, migration, and immune escape by increasing the levels of CD147, MMP9, MMP2, and MMP7. When CD8+ T cells were co-cultured with cell lines expressing different levels of ST6Gal-I, we found that ST6Gal-I upregulation inhibited the T cell proliferation and increased the secretion of IL-10 and TGF-ß1, while secretion of IFN-γ and TNF-α was diminished. In a syngeneic tumor transplant model, ST6Gal-I upregulated Hca-P. In addition, Hepa1-6 cells formed significantly larger tumors and suppressed intratumoral penetration by CD8+ T cells. In combination, these results suggest that ST6Gal-I promotes the immune escape of hepatocarcinoma cells in the tumor microenvironment and highlight the importance of assessing ST6Gal-I status for immunotherapies.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/imunologia , Sialiltransferases/metabolismo , Evasão Tumoral , Animais , Apoptose , Basigina/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glicosilação , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Ácido N-Acetilneuramínico/química , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Int J Med Sci ; 16(3): 470-476, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911281

RESUMO

Hes3 is a basic helix-loop-helix factor gene, which was found to be involved in neural cell differentiation. Expression and clinicopathological significance of Hes3 in non-small cell lung cancer was not clear. In this study, we used immunohistochemistry to examine Hes3 expression in normal human lung and non-small cell lung cancer tissues. Hes3 expression was detected in cytoplasm and nucleus. Hes3 expression in bronchial epithelial cells and epithelial cells of submucosal glands was relatively weak and the positive rate was of 30.3% (10/33). Hes3 expression in non-small cell lung cancer tissues (51.8% (58/112)) was significantly higher than that in normal lung tissues (p < 0.05). Hes3 expression in cancer tissues was significantly associated with poor differentiation, advanced TNM stages, lymph node metastasis, and a shorter patient survival time (p < 0.05). In vitro study showed that overexpression of Hes3 in A549 cells significantly promoted cancer cell proliferation and invasion, while inhibition of Hes3 expression significantly downregulated cancer cell proliferation and invasion (p < 0.05). Western blotting showed that overexpression of Hes3 significantly upregulated expression of Cyclin D1, Cyclin D3, and MMP7 in A549 cells, while inhibition of Hes3 expression in LK2 cells significantly downregulated the expression of these molecules (p < 0.05). These results indicated that Hes3 may contribute to the malignant phenotype of non-small cell lung cancer, possibly through regulation of Cyclin D1, Cyclin D3, and MMP7, and may be a promising cancer marker.


Assuntos
Ciclina D1/metabolismo , Ciclina D3/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Pulmonares/patologia , Metaloproteinase 7 da Matriz/metabolismo , Fatores de Transcrição/metabolismo , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Feminino , Humanos , Estimativa de Kaplan-Meier , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade
6.
J Mol Neurosci ; 68(1): 66-77, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826985

RESUMO

The PAX3 (paired box 3) gene plays an important role in embryonic development, diseases, and cancer formation. Our preliminary studies have shown that PAX3 gene is upregulated in glioma cells, which is associated with a worse prognosis. Moreover, PAX3, by facilitating cell proliferation and invasion and inhibiting cell apoptosis, plays an oncogenic role in glioma. However, the specific molecular mechanism of PAX3 acting as an oncogene in glioma remains unclarified. In the present study, we have found that PAX3 overexpression was observed in high grade glioma and predicted a worse prognosis. PAX3 overexpression did not correlate significantly to IDH1 mutation and MGMT methylation. Moreover, the expression of PAX3 was positively correlated with that of ß-catenin. In U87 glioma cells, PAX3 interacted with ß-catenin, as was confirmed by CO-IP. Besides, PAX3 overexpression promoted cell proliferation and cell cycle progression, while it inhibited cell apoptosis by altering the expressions of important molecules associated with the Wnt signaling pathway, including ß-catenin, Myc, VEGF, cyclinD1, MMP7, and Wnt1. In the meantime, it was also proved that PAX3 correlated to ß-catenin through a negative regulatory mechanism with respect to the promotion of U87 glioma cell proliferation and cell cycle progression and inhibition of the cell apoptosis. Our experiment demonstrated the role of PAX3 in promoting glioma growth and development, possibly by interacting directly with ß-catenin and regulating the Wnt signaling pathway.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Fator de Transcrição PAX3/metabolismo , Via de Sinalização Wnt , Adulto , Idoso , Apoptose , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/metabolismo , Feminino , Glioma/patologia , Humanos , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Pessoa de Meia-Idade , Fator de Transcrição PAX3/genética , Ligação Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína Wnt1/metabolismo , beta Catenina/metabolismo
7.
Int J Biol Sci ; 15(3): 556-567, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745842

RESUMO

Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. Neonatal rat cardiomyocytes (CMs) and CFs were used to verify the protective effect of RA in vitro. Conditioned medium derived from RA-treated CFs were prepared to illustrate the effect of RA on paracrine interplay between CFs and CMs. We found that RA significantly alleviated DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in vivo, which, however, had almost negligible beneficial effect on DOX directly induced cardiomyocyte apoptosis in vitro. Mechanistically, CFs-derived Fas L was responsible for DOX-induced cardiomyocyte apoptosis, and RA treatment could decrease Fas L expression in CFs and its release to the conditioned medium by suppressing nuclear factor of activated T cells (NFAT) activation and metalloproteinase 7 (MMP7) expression, and exerted the anti-apoptotic effect on CMs via CFs. Ionomycin, and activator of NFAT, abrogated RA-mediated protective effect on cardiomyocyte apoptosis and cardiac dysfunction. In summary, RA alleviated cardiomyocyte apoptosis by inhibiting the expression and release of Fas L in CFs via a paracrine manner, moreover, NFAT as well as MMP7 inhibition were responsible for the suppression of Fas L. RA could be a powerful new therapeutic agent to mitigate cardiomyocyte apoptosis, thereby improving DOX-induced cardiotoxicity.


Assuntos
Cinamatos/farmacologia , Depsídeos/farmacologia , Doxorrubicina/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Cardiotoxicidade/metabolismo , Células Cultivadas , Ecocardiografia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Hemodinâmica/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Metaloproteinase 7 da Matriz/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real
8.
Mol Ther ; 27(3): 611-622, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30772143

RESUMO

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Animais , Anticorpos Neutralizantes/metabolismo , Circulação Sanguínea/fisiologia , Microscopia Crioeletrônica , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Miocárdio/patologia
9.
Biochem Biophys Res Commun ; 510(4): 495-500, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30658852

RESUMO

Epithelial-mesenchymal transition (EMT) occurs in the progression of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The hydroxysteroid sulfotransferase 2B1b (SULT2B1b) promotes the proliferation of hepatocarcinoma cells both in vitro and in vivo. However, the correlation between SULT2B1b and the EMT in hepatocytes has not yet been addressed. The present study demonstrated that the SULT2B1b overexpression promoted the EMT process in mouse primary hepatocytes in the absence or presence of TGF-ß1 treatment. Moreover, SULT2B1b interference suppressed the EMT and attenuated the migration and invasion abilities of human hepatocarcinoma BEL-7402 cells by inhibiting the activation of the ß-catenin/MMP-7 pathway. In summary, SULT2B1b enhanced the EMT of hepatocytes and promoted the migration and invasion abilities of BEL-7402 cells by activing the ß-catenin/MMP-7 pathway. Therefore, inhibition of SULT2B1b has therapeutic potential for the treatment of HCC.


Assuntos
Transição Epitelial-Mesenquimal , Metaloproteinase 7 da Matriz/metabolismo , Sulfotransferases/metabolismo , beta Catenina/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Cultivadas , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Via de Sinalização Wnt
10.
Clin Chim Acta ; 490: 55-62, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30517850

RESUMO

The morbidity and mortality associated with acute kidney injury (AKI) remain obstinately high. Early diagnosis is urgently required and should be pursued in at-risk populations. Recently, a newly validated biomarker, matrix metalloproteinase-7 (MMP-7), was reported as a novel indicator for early AKI prediction and a noninvasive surrogate biomarker of kidney function. Monitoring urinary MMP-7 (uMMP-7) levels fills the gaps in early diagnosis of AKI at early onset. However, the lack of available reagents for its rapid detection limits its use. Herein, we established an ultrasensitive and rapid immunomagnetic microparticles-based time-resolved fluoroimmunoassay to measure urinary MMP-7 in AKI patients. The assay time is 30 min. The calibration curve showed high linear correlation (r = 0.9998) with a linearity of detection of 0.063-150 ng mL-1 and lower limit of detection of 0.039 ng mL-1. The coefficient variation of the intra- and inter-assay lower than 5.17%, and the analytical recovery was 99.06%-105.60%. Testing of clinical samples using the proposed assay and a DUOSET@ ELISA kit showed good correlations in the comparison of uMMP-7 levels (r = 0.9541) and uMMP-7/uCreatinine (r = 0.9595). The proposed assay has satisfactory analytical performance and may serve as a promising tool for early diagnosis of AKI.


Assuntos
Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/enzimologia , Imunoensaio/métodos , Limite de Detecção , Imãs/química , Metaloproteinase 7 da Matriz/metabolismo , Microesferas , Diagnóstico Precoce , Humanos , Modelos Lineares , Fatores de Tempo
11.
Clin Biochem ; 63: 85-91, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30414845

RESUMO

OBJECTIVE: To assess the potential impact of mutant ECM amino acids (AA) on melanoma-related matrix metalloproteinase-7 (MMP7) activity. DESIGN AND METHODS: We applied a novel scripted algorithm, based on the MEROPS database, to reveal mutant-dependent sensitivity changes across the cancer genome atlas, melanoma dataset. RESULTS: This approach revealed a strong bias in favor of mutant AA dependent protease sensitivity increases. Thus, melanoma specimens with relatively few mutations had only MMP7 mutant sensitive, ECM peptides. As mutations increased, melanoma specimens included mutant AA representing mostly increased sensitivity and a small but increasing number of mutant AA representing decreased MMP7 sensitivity. There was no detection of melanoma specimens with only decreases in MMP7 sensitivity. Furthermore, melanoma specimens with exclusively increased sensitivity and thereby only a few overall mutations represented reduced T-cell infiltrates and worse outcomes. CONCLUSIONS: Overall, the results indicated that changes in MMP7 sensitivity, attributable to mutant AA, have the potential of identifying patients with distinct survival outcomes as well as patients with cancer specimen immune activity.


Assuntos
Algoritmos , Bases de Dados Genéticas , Matriz Extracelular , Metaloproteinase 7 da Matriz , Melanoma , Mutação , Proteínas de Neoplasias , Linfócitos T/metabolismo , Intervalo Livre de Doença , Matriz Extracelular/genética , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/imunologia , Metaloproteinase 7 da Matriz/metabolismo , Melanoma/genética , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/mortalidade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Taxa de Sobrevida , Linfócitos T/imunologia
12.
J Infect Dis ; 219(4): 633-636, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29920600

RESUMO

Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis-infected C3HeB/FeJ mice. We demonstrate that, compared with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.


Assuntos
Metaloproteinase 7 da Matriz/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose Pulmonar/patologia , Animais , Modelos Animais de Doenças , Feminino , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Camundongos Endogâmicos C3H , Análise de Sobrevida , Tuberculose Pulmonar/mortalidade
13.
FASEB J ; 33(2): 2770-2781, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30303742

RESUMO

Preterm premature rupture of fetal membranes precedes 30-40% of preterm births. Activation of matrix metalloproteases (MMPs) is the one of the major causes of extracellular matrix (ECM) degradation in membrane rupture. Increased cortisol, regenerated by 11ß-hydroxysteroid dehydrogenase 1 in the amnion at parturition, is known to participate in a number of parturition-pertinent events. However, whether cortisol has a role in the regulation of MMPs in the membranes is not known. Here, we addressed this issue using human amnion tissue, the most tensile layer of the membranes. RNA-sequencing revealed that cortisol induced MMP7 expression dramatically in amnion fibroblasts, which was confirmed by real-time quantitative RT-PCR and Western blotting analysis in cortisol-treated amnion explants and fibroblasts. Measurement of collagen IV α5 chain (COL4A5), a substrate for MMP-7, showed that cortisol reduced its extracellular abundance, which was blocked by an antibody against MMP-7. Moreover, increased MMP-7 but decreased COL4A5 abundance was observed in the amnion tissue following labor-initiated spontaneous rupture of membranes. Mechanistic studies showed that cortisol increased the phosphorylation of c-Jun and the expression of c-Fos, the 2 major components of activated protein 1 (AP-1), respectively. The knocking down of c-Fos or c-Jun significantly attenuated the induction of MMP7 expression by cortisol. Chromatin immunoprecipitation assays showed that cortisol stimulated the enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter. The data suggest that induction of MMP7 by cortisol via AP-1 may be a contributing factor to ECM degradation in membrane rupture at parturition.-Wang, L.-Y., Wang, W.-S., Wang, Y.-W., Lu, J.-W., Lu, Y., Zhang, C.-Y., Li, W.-J., Sun, K., Ying, H. Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.


Assuntos
Âmnio/enzimologia , Ruptura Prematura de Membranas Fetais/patologia , Fibroblastos/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hidrocortisona/efeitos adversos , Metaloproteinase 7 da Matriz/metabolismo , Parto , Âmnio/efeitos dos fármacos , Anti-Inflamatórios/efeitos adversos , Células Cultivadas , Ativação Enzimática , Feminino , Ruptura Prematura de Membranas Fetais/induzido quimicamente , Ruptura Prematura de Membranas Fetais/enzimologia , Fibroblastos/efeitos dos fármacos , Humanos , Gravidez
14.
Anticancer Agents Med Chem ; 18(14): 2010-2016, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30501604

RESUMO

BACKGROUND: Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients. METHODS: Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis. RESULTS: MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/ß-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1. CONCLUSION: DKK1 and Wnt/ß-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Maitansina/análogos & derivados , Neoplasias Gástricas/patologia , Trastuzumab/farmacologia , Adenocarcinoma/enzimologia , Adenocarcinoma/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Metaloproteinase 7 da Matriz/genética , Maitansina/farmacologia , Camundongos , Camundongos Nus , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/metabolismo , Regulação para Cima , beta Catenina/metabolismo
15.
Iran J Allergy Asthma Immunol ; 17(5): 485-489, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30518190

RESUMO

Gender medicine is a new era of science which focuses on the impact of sex hormones and gender on normal physiology, pathobiology and clinical features of diseases. In this study we investigated the impact of pregnancy doses of progesterone hormone on the expression of a couple of matrix metalloproteinase (MMPs), which are known to be involved in tissue remodeling of lungs in health and disease, namely MMP7 and 13. Pregnancy maintenance dose of progesterone was administered to female BALB/c mice for 21 and 28 days, the control group received PBS for the same days. After removal of the lungs and RNA extraction, quantitative real-time PCR was done using specific primers for MMP7 and MMP13. We found that progesterone can slightly (not significantly) decrease the expression of MMP13 but had no effect on MMP7. Our results shows that progesterone has minimal effect on the expression of matrix metalloproteinase7 and matrix metalloproteinase 13, but it may still have an effect on corresponding tissue inhibitor of matrix metalloproteinases (TIMPs) or other components of the Extracellular matrix  which remains to be elucidated. Also, the effect of progesterone on these MMPs can be further studied in a fibrosis model.


Assuntos
Matriz Extracelular/metabolismo , Pulmão/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Progesterona/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/patologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Progesterona/administração & dosagem , Inibidores Teciduais de Metaloproteinases/metabolismo
16.
In Vitro Cell Dev Biol Anim ; 54(10): 736-742, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30324243

RESUMO

Monensin is a metal ionophore used as anticancer agent in many types of cancer cells. In this study, therapeutic potential of monensin was evaluated in TFE3 translocated renal cell carcinoma (RCC) cell line UOK146. UOK146 cells were treated with different concentrations of monensin, and cell death was induced as shown by MTT assay. Autophagy was studied by LC3 western, FACS and LC3 puncta formation after monensin treatment. Mitochondrial potential was studied by staining with TMRM and FACS. Antimetastatic potential of monensin was checked by inhibition of wound closure and MMP7 expression at RNA level. Dead and floating cells after the 10 µM monensin treatment were observed under phase contrast microscope. FACS analysis following TMRM staining showed that mitochondrial membrane gets depolarized after monensin treatment. FACS analysis after acridine orange staining showed increased double positive (green and red) cells, and LC3 upregulation and increased LC3 punta displayed autophagy activation in UOK146 cell line after monensin treatment. These findings showed that monensin acts as antiproliferative agent, activating autophagy and downregulates PRCC-TFE3 fusion transcript in Xp11.2 translocated tumor cell line.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Metaloproteinase 7 da Matriz/metabolismo , Monensin/farmacologia , Autofagia/genética , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Metaloproteinase 7 da Matriz/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Folia Histochem Cytobiol ; 56(3): 133-140, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30187906

RESUMO

INTRODUCTION: Endometrium undergoes regular, cyclic tissue remodeling mostly associated to the endocrine system status. It is well-known fact that steroid hormones are strongly responsible for changes in endometrium. The precise mechanism of their action is still under investigation. The aim of the study was to evaluate the expression of metalloproteinases 2 and 7 (MMP-2, -7) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in human endometrium in relation to serum concentrations of estradiol and progesterone during different phases of menstrual cycle. MATERIAL AND METHODS: The study material consisted of 52 biopsy samples; 12 obtained in the proliferative phase, 11 in the secretory phase and 29 during menstruation. Expression of MMP-2, MMP-7 and TIMP-1 was assessed by immunohistochemistry. Serum concentrations of estradiol and progesterone at time of biopsy were evaluated by immunochemistry assay. Results of the study were statistically assessed by linear regression model. RESULTS: Increased serum concentration of estradiol was associated with increased MMP-2 expression in proliferative phase but decreased in secretory phase and during menstruation. No significant relationship was found between progesterone concentration and MMP-2 expression. Moreover, no difference in the expression of MMP-7 and TIMP-1 in the endometrium in relation to hormone levels and menstrual cycle phases were observed. CONCLUSIONS: The results of the study indicate that estradiol influence MMP-2 expression in the endometrium depends on the phase of menstrual cycle. Such relationships were not found for MMP-7 and TIMP-1 and further tests clarifying association between estradiol and MMPs are needed.


Assuntos
Endométrio/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Adulto , Feminino , Humanos , Ciclo Menstrual/metabolismo , Progesterona/metabolismo , Inibidor Tecidual de Metaloproteinase-2/biossíntese
18.
Biomed Pharmacother ; 108: 224-231, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30219680

RESUMO

BACKGROUND: Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy. PURPOSE: We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways. DESIGN/METHODS: Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues. RESULTS: SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-ß expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury. CONCLUSION: The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-ß. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.


Assuntos
Ácidos Cumáricos/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Bleomicina , Líquido da Lavagem Broncoalveolar/citologia , Ácidos Cumáricos/farmacologia , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Hidroxiprolina/metabolismo , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Metaloproteinase 7 da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/sangue , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/metabolismo , Ganho de Peso/efeitos dos fármacos
19.
Mol Carcinog ; 57(12): 1803-1815, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30175866

RESUMO

The biological role and underlying mechanism of action of zinc-finger protein 326 (ZNF326) in malignant tumors, including breast cancer, are still not clear. In this study, we detected high expression of ZNF326 in breast cancer specimens (60/111, 54.1%) and breast cancer cell lines (7/7); the expression level of ZNF326 was inversely associated with advanced pTNM stage (P = 0.002), positive lymph node metastasis (P = 0.004), poor prognosis in patients with breast cancer (P = 0.0097), and ER/PR/Her2 status (P = 0.013). Meanwhile, the ectopic expression of ZNF326 significantly upregulated MMP7, EMT-related proteins (Snail and Slug), and cell cycle-related proteins (cyclinA2 and cyclinB1); downregulated E-cadherin expression; and promoted the proliferation and invasiveness of breast cancer cells both in vivo and in vitro. Mechanistically, co-immunoprecipitation and immunofluorescence assays both demonstrated that ZNF326 interacted with deleted in breast cancer-1 (DBC1) in breast cancer cells. Additionally, DBC1 knockdown eliminated the up-regulation of MMP7, EMT-related proteins, and cell cycle-related proteins as well as the enhanced proliferation and invasiveness induced by ZNF326. Therefore, we concluded that ZNF326 is highly expressed in breast cancer, is associated with poor prognosis, and plays a vital role in promoting the malignant phenotype of breast cancer cells by interacting with DBC1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Regulação para Cima , Animais , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Células MCF-7 , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Análise de Sobrevida
20.
Biomed Pharmacother ; 107: 484-494, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30107344

RESUMO

PURPOSE: To study the influence of resveratrol on proliferation, migration and invasion of multiple myeloma (MM) cells through the long noncoding RNA (lncRNA) NEAT1 (nuclear enriched abundant transcript 1)-modulated Wnt/ß-catenin signaling pathway. METHODS: Microarray analysis was used to screen aberrantly expressed lncRNAs from MM cells and normal plasmocytes. The effects of NEAT1 overexpression/silencing or resveratrol treatment on MM cell (U266 and LP1) proliferation, migration and invasion were investigated using CCK-8 (Cell Counting Kit-8), wound healing and Transwell invasion assays. Expression of Wnt/ß-catenin related proteins and unfolded protein response (UPR)-related proteins was detected by western blot. RESULTS: lncRNA NEAT1 was highly expressed in MM cells, which could be significantly inhibited by resveratrol. NEAT1 overexpression induced proliferation, migration and invasion of MM cells, while resveratrol counteracted its effect. NEAT1 upregulated protein expression in the Wnt/ß-catenin signaling pathway, while resveratrol reversed the negative effect of NEAT1 overexpression on MM cells through the Wnt/ß-catenin signaling pathway, and hence suppressed MM cell reproduction, migration and invasion. Resveratrol could also restrain unfolded protein response in MM cells. CONCLUSION: Resveratrol downregulated the expression of lncRNA NEAT1 in MM cells and inhibited proliferation, migration and invasion of MM cells by suppressing the Wnt/ß-catenin signaling pathway and unfolded protein response.


Assuntos
Movimento Celular/efeitos dos fármacos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , RNA Longo não Codificante/genética , Resveratrol/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Metaloproteinase 7 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/metabolismo , Survivina/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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