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1.
Anticancer Res ; 40(6): 3097-3108, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487604

RESUMO

BACKGROUND/AIM: C-C motif chemokine ligand 18 (CCL18) is overexpressed in the microenvironment of tumors, promotes invasion and metastasis and is thus important for the therapeutic outcome of many tumor entities. The Gs-coupled seven-transmembrane receptor GPR30 is known as both a CCL18 and an estrogen receptor; its activation by estradiol leads to a transactivation of membrane-tethered pro-heparin-binding EGF-like growth factor and the MAPK/ERK pathway. We examined whether this signaling pathway remains the same under CCL18 stimulation, as opposed to estradiol stimulation. MATERIALS AND METHODS: We investigated the effects of CCL18 on the lung cancer cell line A549, that show low GPR30 expression and the breast cancer cell lines MCF-7, that has high GPR30 expression and MDA-MB-231. These cells were stimulated in different media with CCL18 and then analyzed by qPCR, In-Cell Western®, western blot and ELISA. RESULTS: Many similarities on the effect of CCL18 on the already known estradiol-activated signaling pathway via the G protein-coupled estrogen receptor GPR30 were identified. GPR30 is involved in the expression of matrix metalloproteinases (MMPs), which may play a role in the transactivation of ERK-1/-2 via the cleavage of membrane-bound HB-EGF, via Src-related tyrosine kinases and Gßγ-subunits. With increasing CCL18 concentration, the expression of MMP7 decreased in A549 cells. With decreasing estrogen content of the medium, there was an increasing effect of CCL18 on the inhibition of the relative expression of MMP7. Inhibition of GPR30 with G15 also resulted in a decrease in the relative expression of MMP7, irrespective of the subsequent stimulation with CCL18. This is a rather unexpected result, because the estrogen estradiol and CCL18 both activate GPR30. MCF-7 cells which express more GPR30 did not show any dependence of the relative MMP7 expression on CCL18 except in estrogen-free FCS medium. CCL18 induced an increased relative ERK activation in In-Cell western (ICW) at A549 cells. Stimulation with CCL18 caused decreased ERK activation with simultaneous inhibition of adenylate cyclase in MCF-7. However, stimulation with CCL18 and simultaneous inhibition of cyclooxygenase in MCF-7 resulted in increased ERK activation. In A549, stimulation with CCL18 and co-incubation with dbcAMP resulted in decreased ERK activation in both ICW and Western blot. CONCLUSION: In summary, the Gs-coupled receptor GPR30 plays an important role in the signaling pathway of CCL18. CCL18 and estradiol may not lead to the same signaling pathway after activating GPR30.


Assuntos
Quimiocinas CC/metabolismo , Estradiol/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células A549 , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiocinas CC/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Metaloproteinase 7 da Matriz/biossíntese , Metaloproteinase 7 da Matriz/genética , Fosforilação , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Transdução de Sinais
2.
Anticancer Res ; 40(2): 695-702, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014910

RESUMO

BACKGROUND/AIM: Few studies have examined the genetic role of matrix metalloproteinases (MMPs) to early detection or prediction in gastric cancer development. In this study, the contribution of MMP7 promoter (A-181G and C-153T) polymorphic genotypes to gastric cancer risk in Taiwanese was investigated for the first time. MATERIALS AND METHODS: A total of 121 cases and 363 controls were enrolled and their MMP7 genotypes at A-181G and C-153T were examined by polymerase chain reaction-restriction fragment length polymorphism methodology using genomic DNA from serum. RESULTS: The GG genotype at MMP7 A-181G was found to represent a risk factor for gastric cancer, especially among smokers. No individual with variant genotype carrier at MMP7 C-153T was found among this Taiwanese population. CONCLUSION: The G allele of MMP7 A-181G may serve as an early predictor for gastric cancer risk in Taiwanese; other gastric cancer markers are still urgently needed.


Assuntos
Metaloproteinase 7 da Matriz/genética , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Taiwan
3.
Am J Kidney Dis ; 75(3): 384-393, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31606236

RESUMO

RATIONALE & OBJECTIVE: A major challenge in the management of immunoglobulin A nephropathy (IgAN) is the inability to identify patients at high risk for disease progression at an early stage. Our objective was to determine whether urinary matrix metalloproteinase 7 (MMP-7) is a promising predictor for IgAN progression and whether its addition to clinical data at the time of biopsy improves risk prediction. STUDY DESIGN: Prospective observational cohort study in China. SETTING & PARTICIPANTS: 946 Chinese patients with IgAN followed up for a median of 40 months in 1 clinical center serving as the training set (n=554) and for 28 months in a second clinical center serving as the validation set (n = 392). PREDICTORS: Urinary MMP-7 and 7 previously reported biomarkers measured at the time of kidney biopsy and a score of histologically defined disease severity (MEST-C). OUTCOMES: IgAN progression was defined as a composite of >40% loss of estimated glomerular filtration rate, kidney failure, or death. ANALYTICAL APPROACH: Cox proportional hazard models adjusted for clinical characteristics, kidney function, relevant medications, and MEST-C score. Risk classification statistics were calculated for IgAN progression at 3 years, including C statistic, net reclassification index, and integrated discrimination index. RESULTS: High levels (>3.9µg/g of creatinine) of urinary MMP-7 were associated with a 2.7-fold higher risk for IgAN progression in adjusted analyses. Urinary MMP-7 level outperformed (C statistic, 0.78) levels of urinary angiotensinogen (C statistic, 0.75), epidermal growth factor (C statistic, 0.75), kidney injury molecule 1 (C statistic, 0.68), and serum galactose-deficient IgA1 (C statistic, 0.59) for predicting IgAN progression. The addition of urinary MMP-7 level to a model with clinical data from the time of biopsy (estimated glomerular filtration rate, mean arterial blood pressure, and proteinuria) and MEST-C score significantly improved the C statistic from 0.79 to 0.85, improved the 3-year risk prediction of IgAN progression (from 0.84 to C statistic of 0.90), and improved risk reclassification (category-free net reclassification improvement, 0.60). The predictive performance of urinary MMP-7 level, alone or combined with clinical data, was consistent in the external validation set. LIMITATIONS: Lack of validation in other ethnic populations. CONCLUSIONS: In this study cohort, urinary MMP-7 level is an independent predictor of IgAN progression. The addition of urinary MMP-7 level to MEST-C score and clinical data at the time of biopsy significantly improved risk prediction of IgAN progression.


Assuntos
Glomerulonefrite por IGA/urina , Rim/patologia , Metaloproteinase 7 da Matriz/urina , Adulto , Biomarcadores/urina , Biópsia , Progressão da Doença , Feminino , Seguimentos , Glomerulonefrite por IGA/diagnóstico , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
4.
Biomed Pharmacother ; 121: 109662, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810124

RESUMO

Currently, there is no effective method to prevent renal interstitial fibrosis after acute kidney injury (AKI). In this study, we established and screened a new renal interstitial fibrosis rat model after cisplatin-induced AKI. Our results indicated that rats injected with 4 mg/kg cisplatin once a week for two weeks after firstly administrated with 6.5 mg/kg loading dose of cisplatin could set up a more accurate model reflecting AKI progression to renal interstitial fibrosis. Then, we investigated the effects and possible mechanisms of human umbilical cord blood mononuclear cells (hUCBMNCs) on renal tubular interstitial fibrosis after cisplatin-induced AKI. In rats injected with hUCBMNCs for four times, level of matrix metalloproteinase 7 (MMP-7) in serum and urine, urinary albumin/creatinine ratio, tubular pathological scores, the relative collagen area of the tubulointerstitial region, endoplasmic reticulum dilation and the mitochondrial ultrastructural damage were significantly improved. The level of reactive oxygen species, α-smooth muscle actin (α-SMA), [NOD]-like pyrin domain containing protein 3 and cleaved-Caspase 3 in renal tissue decreased significantly. However, in rats injected with hUCBMNCs for two times, no significant difference was discovered in MMP-7 levels and urinary albumin/creatinine ratio. Although expression of α-SMA and the percentage areas of collagen staining in tubulointerstitial tissues were ameliorated in rats injected with hUCBMNCs for two times, the effects were significantly weaker than those in rats injected with hUCBMNCs for four times. Taken together, our study constructed a highly efficient, duplicable novel rat model of renal fibrosis after cisplatin-induced AKI. Multiple injections of hUCBMNCs may prevent renal interstitial fibrosis after cisplatin-induced AKI.


Assuntos
Cisplatino/efeitos adversos , Sangue Fetal/citologia , Túbulos Renais/patologia , Leucócitos Mononucleares/citologia , Substâncias Protetoras/metabolismo , Cordão Umbilical/citologia , Actinas/metabolismo , Lesão Renal Aguda/sangue , Lesão Renal Aguda/complicações , Lesão Renal Aguda/urina , Animais , Peso Corporal , Caspase 3/metabolismo , Creatinina/sangue , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/ultraestrutura , Masculino , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/urina , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
5.
In Vivo ; 34(1): 51-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882462

RESUMO

BACKGROUND/AIM: In literature, few studies have examined the diagnostic or prognostic potential of matrix metalloproteinases (MMP) in pterygium, whose formation and progression are closely related to imbalance in the extracellular microenvironment. In this study, we investigated the contribution of MMP7 promoter (A-181G and C-153T) polymorphic genotypes to pterygium risk. MATERIALS AND METHODS: A total of 134 cases and 268 controls were collected and their MMP7 genotypes at A-181G and C-153T were examined by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The AA, AG and GG genotypes at MMP7 promoter A-181G were non-significantly differentially distributed between the two groups at 85.8, 11.2 and 3.0%, respectively, in pterygium cases and 88.4, 9.7 and 1.9% in controls, respectively (p for trend=0.6822). There was no polymorphic genotype for MMP7 C-153T among our Taiwanese cohort. CONCLUSION: A-181G and C-153T genotypes at MMP7 do not have a direct role in determining Taiwanese susceptibility to pterygium.


Assuntos
Predisposição Genética para Doença/genética , Metaloproteinase 7 da Matriz/genética , Pterígio/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Fatores de Risco
6.
Dis Markers ; 2019: 9217571, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827648

RESUMO

Aims: Early detection of patients at high risk for progressive acute kidney injury (AKI) after cardiac surgery remains a major challenge. We aim to evaluate the utility of urinary matrix metalloproteinase-7 (uMMP-7) and other reported biomarkers for predicting AKI progression during postoperative hospital stay. Methods: We conducted a prospective, multicenter cohort study in 121 adult patients with stage 1 or 2 AKI after cardiac surgery. uMMP-7 and other well-reported biomarkers (uIL-18, uNGAL, and UACR) were measured at time of AKI clinical diagnosis. The primary outcome is the progression of AKI after cardiac surgery, defined as worsening of AKI stage (stage 1 to either stage 2 or stage 3 or from stage 2 to stage 3). Results: A level of uMMP-7 > 7.8 µg/g Cr at time of AKI diagnosis conveyed an 8-fold risk of AKI progression as compared to those with uMMP-7 < 2.7 µg/g after adjusting for clinical risk factors. The performance of uMMP-7 for predicting progressive AKI was good with an AUC of 0.80. The combination of uMMP-7 and IL-18 produces the greatest AUC for predicting progressive AKI. Addition of uMMP-7 to the clinical risk factor model significantly improved risk reclassification for AKI progression. Conclusions: uMMP-7, measured at time of AKI clinical diagnosis, is a novel biomarker for predicting the progression of AKI after cardiac surgery. Adding uMMP-7 to the clinical risk factor model may be used as a noninvasive approach to identify a subpopulation that is at high risk for progressive AKI after cardiac surgery.


Assuntos
Lesão Renal Aguda/diagnóstico , Biomarcadores/urina , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias/cirurgia , Metaloproteinase 7 da Matriz/urina , Complicações Pós-Operatórias , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/urina , Feminino , Seguimentos , Cardiopatias/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco
7.
Arq Bras Cir Dig ; 32(3): e1449, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31644669

RESUMO

INTRODUCTION: The matrix metalloproteinase-7 (MMP-7) gene -181A>G polymorphism has been reported to be associated with colorectal cancer (CRC) and gastric cancer (GC) susceptibility, yet the results of these previous results have been inconsistent or controversial. AIM: To elaborate a meta-analysis to assess the association of -181A>G polymorphism of MMP-7 with CRC and GC risk. METHODS: Published literature evaluating the association from PubMed, Web of Science, Google Scholar and other databases were retrieved up to April 25, 2018. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS: A total of 19 case-control studies, which included eleven studies on CRC (2,169 CRC cases and 2,346 controls) and eight studies on GC (1,545 GC cases and 2,366 controls) were identified. There was a significant association between MMP-7 -181A>G polymorphism and GC risk under the homozygote model (GG vs. AA: OR=1.672, 95% CI 1.161-2.409, p=0.006) and the recessive model (GG vs. GA+AA: OR=1.672, 95% CI 1.319-2.554, p=0.001), but not with CRC. By subgroup analysis based on ethnicity, an increased risk of CRC and GC was found only among Asians. CONCLUSIONS: This meta-analysis suggests that MMP-7 -181A>G polymorphisms is associated with GC risk, but not with CRC. However, our results clearly showed that the MMP-7 -181A>G polymorphism significantly increased the risk of CRC only in Asians.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Metaloproteinase 7 da Matriz/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/etnologia , Humanos , Razão de Chances , Fatores de Risco
8.
Pediatrics ; 144(5)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604829

RESUMO

BACKGROUND: The overlapping features of biliary atresia (BA) and other neonatal cholestasis with alternative causes (non-BA) have posed challenges for diagnosis. Matrix metalloproteinase-7 (MMP-7) has been reported to be promising in diagnosing BA. We aimed to validate the diagnostic accuracy of MMP-7 for BA in a large population sample. METHODS: We enrolled 288 patients with neonatal obstructive jaundice from March 2017 to October 2018. Serum MMP-7 levels were measured by using an enzyme-linked immunosorbent assay. Receiver operating characteristic curves were constructed, and decision curve analysis was done. A Pearson correlation coefficient test was conducted to assess the correlation between MMP-7 levels and other characteristics. RESULTS: The median serum MMP-7 levels were 38.89 ng/mL (interquartile range: 22.96-56.46) for the BA group and 4.4 ng/mL (interquartile range: 2.73-6.56) for the non-BA group (P < .001). The area under the receiver operating characteristic curve value was 0.9829 for MMP-7, and the sensitivity, specificity, positive predictive value, and negative predictive value were 95.19%, 93.07%, 97.27%, and 91.43%, respectively, at a cutoff value of 10.37 ng/mL. When MMP-7 was combined with γ glutamyl transferase, the diagnostic accuracy was slightly improved without significance when compared with MMP-7 alone and had an area under the curve of 0.9880 (P = .08). Decision curve analysis also showed potential for MMP-7 to be used for clinical applications. A significant correlation was found with fibrosis stage from liver biopsy (R = 0.47; P < .001). CONCLUSIONS: MMP-7 demonstrated good accuracy in diagnosing BA and holds promise for future clinical application. Furthermore, its correlation with liver fibrosis indicated its potential use as a therapeutic target or prognostic biomarker.


Assuntos
Atresia Biliar/diagnóstico , Icterícia Neonatal/sangue , Metaloproteinase 7 da Matriz/sangue , Área Sob a Curva , Atresia Biliar/sangue , Atresia Biliar/complicações , Biomarcadores/sangue , Biópsia , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/normas , Técnicas de Apoio para a Decisão , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Icterícia Neonatal/etiologia , Fígado/patologia , Masculino , Curva ROC , Sensibilidade e Especificidade
9.
Int J Biol Markers ; 34(3): 292-301, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31578137

RESUMO

OBJECTIVE: Tissue inhibitor of metalloproteinases 1 (TIMP-1) and matrix metalloproteinase 7 (MMP-7) were reported to have potent growth promoting activity. Lack of balance between MMPs and TIMPs is an important factor in the development of gastrointestinal malignancies. METHODS: We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of TIMP-1 and MMP-7 were measured immunochemically and compared with standard tumor markers carcinoembryonic antigen and CA19-9. RESULTS: Serum levels of TIMP-1 and MMP-7 were significantly higher in patients with colorectal cancer compared to healthy controls (both, P < 0.001). TIMP-1 and MMP-7 correlate with the presence of colon involvement (P = 0.001; P = 0.012) and the presence of liver metastases (P = 0.002; P = 0.037), and negatively correlate with pulmonary metastases (P = 0.014; P = 0.005). MMP-7 had similar sensitivity and the same specificity as carcinoembryonic antigen. TIMP-1 and MMP-7 had better sensitivity than CA19-9. TIMP-1 and MMP-7 level correlate with worse outcome (P = 0.002). CONCLUSION: The results indicate that TIMP-1 and MMP-7 are effective biomarkers in patients with metastatic colorectal cancer with good sensitivity. TIMP-1 and MMP-7 levels strongly correlate with the extent of liver disease and have prognostic value.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/genética , Metaloproteinase 7 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
10.
Clin Exp Med ; 19(4): 565-570, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31576476

RESUMO

The circulating matrix metalloproteinase-7 (MMP-7) levels are associated with the risk of bladder cancer (BC). MMP-7 gene -181A/G polymorphism may influence the expression of MMP-7 by affecting the transcriptional activity. A case-control study comprising 355 BC patients and 435 age- and gender-matched healthy controls was conducted in a Chinese Han population. The genotype of MMP-7 gene -181A/G polymorphism was determined by using polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that MMP-7 gene -181A/G polymorphism increased the risk of BC under the homozygous and allelic models. However, no association between MMP-7 gene -181A/G polymorphism and BC risk was obtained after adjusting for age, gender, smoking habits and drinking habits. Subgroup analyses showed MMP-7 gene -181A/G polymorphism was associated with increased risk for BC among the smokers and drinkers. Furthermore, AG or GG genotype of -181A/G polymorphism was associated with larger tumor size and lymphatic metastasis in BC patients. To sum up, MMP-7 gene -181A/G polymorphism is not associated with the susceptibility to BC. However, subgroup analyses obtain significant association among the groups of smokers and drinkers. Larger studies in other ethnic groups are needed to ascertain the contribution of MMP-7 gene -181A/G polymorphism to BC risk.


Assuntos
Predisposição Genética para Doença , Genótipo , Metaloproteinase 7 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/genética , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Feminino , Técnicas de Genotipagem , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Medição de Risco
11.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652949

RESUMO

Cleavage of E-cadherin and the resultant weakness in the cell-cell links in the laryngeal epithelium lining is induced by exposure to acidic contents of the refluxate. Herein, we aimed to evaluate the role of matrix metalloproteinases (MMPs) in inducing E-cadherin level changes following acid exposure to the human pharyngeal mucosal cells. E-cadherin levels were inversely correlated with the duration of acid exposure. Treatment with actinonin, a broad MMP inhibitor, inhibited this change. Immunocytochemical staining and transepithelial permeability test revealed that the cell surface staining of E-cadherin decreased and transepithelial permeability increased after acid exposure, which was significantly inhibited by the MMP inhibitor. Among the various MMPs analyzed, the mRNA for MMP-7 in the cellular component was upregulated, and the secretion and enzymatic activity of MMP-7 in the culture media increased with the acid treatment. Consequently, MMP-7 plays a significant role in the degradation of E-cadherin after exposure to a relatively weak acidic condition that would be similar to the physiologic condition that occurs in Laryngopharyngeal reflux disease patients.


Assuntos
Caderinas/metabolismo , Refluxo Laringofaríngeo/patologia , Metaloproteinase 7 da Matriz/metabolismo , Adulto , Meios de Cultura/química , Meios de Cultura/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio , Refluxo Laringofaríngeo/metabolismo , Masculino , Metaloproteinase 7 da Matriz/química , Metaloproteinase 7 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Pessoa de Meia-Idade , Faringe/citologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
12.
Biomed Pharmacother ; 118: 109253, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545288

RESUMO

OBJECTIVE: To investigate the regulation mechanism of baicalin on triple negative breast cancer (TNBC)'s biological network by a systematic biological strategy and cytology experiment. METHODS: A systematic biological methodology is utilized to predict the potential targets of baicalin, collect the genes of TNBC, and analyze the TNBC and baicalin's network. After the systematic biological analysis is performed, the cytology experiment, real-time quantitative PCR (qPCR) is used to validate the key biological processes and signaling pathways. RESULTS: After systematic biological analysis, two networks were constructed and analyzed: (1) TNBC network; (2) Baicalin-TNBC protein-protein interaction (PPI) network. Several TNBC-related, treatment-related targets, clusters, signaling pathways and biological processes were found. Cytology experiment shows that baicalin can inhibit the proliferation, migration and invasion of breast cancer MDA-MB-231 cells in vitro (P < 0.05). The results of qPCR showed that baicalin increase the expression of E-cadherin mRNA, and decrease the expression of vimentin, ß-catenin, c-Myc and MMP-7 mRNA in LPS-induced breast cancer MDA-MB-231 cells (P < 0.05). CONCLUSION: Baicalin may achieve anti-tumor effects through regulating the targets, biological processes and pathways found in this research.


Assuntos
Flavonoides/uso terapêutico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Humanos , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Invasividade Neoplásica , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 317(5): G682-G693, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433212

RESUMO

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFßR2 gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein ß-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of "target-specific" therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Animais , Caderinas/genética , Caderinas/metabolismo , Vacinas Anticâncer/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Gastrinas/uso terapêutico , Macrófagos/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Microambiente Tumoral , beta Catenina/genética , beta Catenina/metabolismo
14.
Int J Biochem Cell Biol ; 116: 105590, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442606

RESUMO

Long noncoding RNAs (lncRNAs) play an essential role in cancer development. However, the contribution of the lncRNA LINC00997 to kidney renal clear cell carcinoma (KIRC) has not been thoroughly elucidated to date. In this study, we examined the expression and biological effect of LINC00997 in KIRC development. We also investigated the potential mechanism underlying the observed effects. We found that LINC00997 is highly expressed in multiple carcinomas, being highest in stage IV KIRC in our RNA-Seq datasets. In addition, our data demonstrated that in KIRC patients, higher levels of LINC00997 are correlated with lower overall survival (OS) and disease-free survival (DFS) rates. In 18 cases of KIRC, we found that LINC00997 expression was greater in cancer tissues and metastases than in normal tissues. These results revealed that S100A11 is positively associated with LINC00997 in KIRC, which is positively correlated with metastasis-associated molecules VIM, MMP2 and MMP7. Our in vitro wound healing assay and Transwell tests demonstrated that interfering with either LINC00997 or S100A11 expression reduced migration of 786-O cells by inhibiting VIM, MMP2 and MMP7 expression. Importantly, we verified LINC00997 and STAT3 binding by RIP and determined that both LINC00997 and STAT3 bind to the S100A11 promoter, as shown by dual-luciferase reporter gene assay. In addition, inhibiting LINC00997 or STAT3 expression attenuated S100A11 levels. Consequently, the LINC00997-STAT3-S100A11 axis may promote the development of KIRC, and LINC00997 may represent a potential prognostic biomarker and therapeutic target for KIRC patients.


Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , RNA Longo não Codificante/genética , Proteínas S100/genética , Fator de Transcrição STAT3/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Metástase Linfática , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Ligação Proteica , RNA Longo não Codificante/metabolismo , Proteínas S100/metabolismo , Fator de Transcrição STAT3/metabolismo , Saporinas/genética , Saporinas/metabolismo , Transdução de Sinais , Análise de Sobrevida , Vimentina/genética , Vimentina/metabolismo
15.
Anticancer Res ; 39(8): 4485-4490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366549

RESUMO

BACKGROUND/AIM: Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions. MATERIALS AND METHODS: The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining. RESULTS: MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups. CONCLUSION: MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN.


Assuntos
Metaloproteinase 1 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Intraductais Pancreáticas/genética , Idoso , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Intraductais Pancreáticas/epidemiologia , Neoplasias Intraductais Pancreáticas/patologia
16.
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
17.
BMC Cancer ; 19(1): 685, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299935

RESUMO

BACKGROUND: Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC). METHODS: Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7. RESULTS: We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50. CONCLUSION: Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 7 da Matriz/genética , NF-kappa B/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo
18.
Mol Biol Rep ; 46(5): 5123-5130, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342296

RESUMO

The disease phenotype in biliary atresia (BA) is caused by a fibro-inflammatory process leading to destruction of cholangiocytes, obstruction of ductular pathways and eventual progression to liver cirrhosis. The first line of management is a Kasai portoenterostomy (KPE) followed by liver transplantation (LT) in some children. Several factors have been postulated to affect the outcome of KPE and/or the subsequent progression of liver disease. However, no biomarkers have been identified in the liver for BA. We aimed to address this deficit. Whole transcriptome mRNA sequencing was performed for 29 samples (25 BA and 4 Controls) to identify the candidate genes predicting the prognosis of KPE. These results were further confirmed with quantitative Realtime PCR (qPCR). Analysis from RNA-sequencing data identified matrix metalloproteinase7 (MMP7) and phosphoenolpyruvate carboxykinase (PCK1) as potential determinants of the outcome of KPE. MMP7 expression was significantly elevated in patients who failed to clear jaundice after KPE as well as in patients with End Stage Liver Disease (ESLD). In contrast, PCK1 level was upregulated in patients who had successful KPE, while there was a significant down regulation in patients who failed KPE. MMP7 and PCK1 expression patterns had an inverse relation to the outcome of KPE and hence could potentially be used as biomarkers to predict KPE outcome and disease progression, enabling clinicians to design new treatment strategies for BA.


Assuntos
Atresia Biliar/cirurgia , Perfilação da Expressão Gênica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metaloproteinase 7 da Matriz/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Regulação para Cima , Atresia Biliar/genética , Pré-Escolar , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Portoenterostomia Hepática , Prognóstico , Estudos Prospectivos , Análise de Sequência de RNA , Resultado do Tratamento , Sequenciamento Completo do Exoma
19.
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
20.
Circ Res ; 125(4): 414-430, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31221024

RESUMO

RATIONALE: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated. OBJECTIVE: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure. METHODS AND RESULTS: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-ß, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-ß and augments its intracellular signaling. CONCLUSIONS: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.


Assuntos
Diástole , Imunoglobulinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/metabolismo , Miofibroblastos/metabolismo , Regeneração , Animais , Células CHO , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Cricetinae , Cricetulus , Células HEK293 , Humanos , Imunoglobulinas/genética , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Miofibroblastos/fisiologia , Ligação Proteica
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