HNF4G stimulates the development of pancreatic cancer by promoting IGF2BP2 transcription

Objective Pancreatic cancer is a devastating and lethal malignancy. Our study investigated the effective mechanism of HNF4G on pancreatic cancer cell functions through the IGF2BP2 transcription. Methods HNF4G and IGF2BP2 expressions in pancreatic cancer were examined. The relationship between HNF4G expression and pancreatic cancer patients’ clinicopathological characteristics was evaluated. After interfering with HNF4G expression in pancreatic cancer cells, the cell proliferative, migratory, and invasive capabilities were evaluated. Also, the expression of proliferation-related gene PCNA and migration and invasion-related gene MMP2 was determined. The binding relation between HNF4G and HNF4G promoter was forecasted and testified. A tumorigenesis assay in nude mice was performed to detect the HNF4G interference’s effect on the subcutaneous tumorigenic capacity of pancreatic cancer cells. Results HNF4G and IGF2BP2 expressions were up-regulated in pancreatic cancer. Specifically, interfering with HNF4G inhibited PANC-1 cell proliferative, invasive and migratory behaviors, and decreased PCNA and MMP2 expression. Mechanistically, HNF4G as a transcription factor could specifically bind to IGF2BP2 and promote its expression. Rescue assay findings showed that IGF2BP2 overexpression could reverse the inhibiting effect of HNF4G interference on pancreatic cancer cells. For the in vivo finding, interfering HNF4G expression retarded the subcutaneous tumorigenic ability of pancreatic cancer cells. Conclusion We summarize that HNF4G as a transcription factor regulates IGF2BP2 expression to promote pancreatic cancer cell proliferation and migration capacities (AU)

GSN synergies with actin-related transfer molecular chain to promote invasion and metastasis of HCC

Background Previous studies have shown that the ability of tumor cells to move and migrate is related to the molecular chain pathway mediated by actin. This study focused on the molecular mechanism of gelsolin (GSN) as an important actin-binding protein in promoting HCC invasion and metastasis. Methods The relationship between GSN expression and clinical characteristics was observed by immunohistochemistry (IHC). In vitro and in vivo experiments confirmed the role of GSN in HCC metastasis. Dual-immunoprecipitation (IP), immunofluorescence (IF), western blotting, and the gelatinase activity assay were used to investigate the mechanism of GSN-promoting metastasis. PEX fusion proteins were used to intervene in the transfer molecular chain. Results Our study found that GSN promoted HCC invasion and metastasis through its synergistic effect with actin-related transfer molecular chain (actin-CD44-MMPs). Concretely, as an important binding molecule of actin, GSN activated MMP2 by interacting with MMP14. Furthermore, CD44 might be a key node in the above-mentioned mechanism. The use of MMP14 domain (PEX fusion protein) to competitively bind to CD44 helped to inhibit the activation of downstream MMP2. Conclusions GSN played crucial roles in HCC metastatic process. An improved understanding of the multiple effects of GSN in HCC might facilitate a deeper appreciation of GSN as an important HCC regulator. The study identified GSN and its regulated transfer molecular chain as potential therapeutic targets for HCC (AU)

Use of nimotuzumab combined with cisplatin in treatment of nasopharyngeal carcinoma and its effect on expressions of VEGF and MMP-2

Purpose This paper aims to observe the expressions of VEGF and MMP-2 in patients with nasopharyngeal carcinoma treated by nimotuzumab combined with cisplatin. Methods Altogether, 104 patients with nasopharyngeal carcinoma treated in our hospital from April 2014 to August 2016 were selected as research subjects. Among them, 50 patients treated with cisplatin were divided into a control group and 54 patients treated with nimotuzumab combined with cisplatin were divided into an observation group. The two groups of patients were compared in terms of efficacy after treatment and incidence of adverse reactions. Changes of serum VEGF and MMP-2 concentrations before and after treatment were detected using enzyme-linked immunosorbent assay (ELISA), and the 3-year overall survival (OS) of patients was observed. Results Compared with the control group, patients in the observation group had significantly higher total remission rate (RR) (P < 0.05) and significantly lower incidence of adverse reactions (P < 0.05). Before treatment, there was no significant difference between the observation and control groups in the concentrations of VEGF and MMP-2 (P > 0.05). After treatment, the concentrations in the two groups were significantly lower than those before treatment (P < 0.05), and the concentrations in the observation group were significantly lower than those in the control group (P < 0.05). There was no significant difference in the 3-year OS between the observation and control groups (P > 0.05). Conclusions Nimotuzumab combined with cisplatin could improve the conditions of patients with nasopharyngeal carcinoma. After treatment, the expression of VEGF and MMP-2 decreased significantly. We speculated that it improves the survival rate of patients by reducing the expression of VEGF and MMP-2 (AU)

PPARγ regulates inflammatory reaction by inhibiting the MAPK/NF-κB pathway in C2C12 skeletal muscle cells

Excessive exercise induces an inflammatory response caused by oxidative stress, which delays recovery of damaged muscle fibers. The reduction of inflammatory response is important for skeletal muscle homeostasis. Peroxisome proliferator-activated receptor gamma (PPARγ) is an anti-inflammatory molecule, but the role of PPARγ in skeletal muscle as anti-inflammatory activity is not clear. Thus, this study examined the anti-inflammatory role of PPARγ against H2O2-induced oxidative stress in skeletal muscle. Sprague Dawley (SD) rats were exercised on a treadmill to induce oxidative stress. In vitro oxidative stress was evaluated in differentiated C2C12 cells stimulated using 200 μM H2O2. Inflammation-related molecules were determined by immunohistochemistry and Western blot analysis. Expressions of the inflammatory molecules tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP-2) in muscles of the acute exercise group were highly increased. PPARγ was also highly expressed in these muscles. These inflammatory molecules were also markedly increased in C2C12 cells with H2O2 stimulation. However, PPARγ overexpression in C2C12 transfected by Ad/PPARγ dramatically reduced the inflammatory molecules. PPARγ also enhanced the anti-oxidants molecules like Cu/Zn-SOD, Mn-SOD, and hemeoxygenase-1 by reducing the generation of ROS, even in the presence of H2O2. PPARγ displayed dual anti-inflammatory and anti-oxidant roles by inhibiting the mitogen-activated protein kinase (MAPK) pathway and translocation of nuclear transcriptional factor-κB (NF-κB) from the cytosol to the nucleus. These results demonstrate a potential role of PPARγ in protecting muscle fibers against oxidative stress caused by excessive acute exercise due to its anti-inflammatory and anti-oxidant activity exerted by inhibition of the MAPK/NF-κB pathway (AU)

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A common effect of angiotensin II and relaxin 2 on the PNT1A normal prostate epithelial cell line

The prostate gland is a part of the male reproductive tract which produces both angiotensin II (Ang II) and relaxin 2 (RLN2). The present study analyzes the effect of both these peptide hormones at concentration 10−8M on viability, proliferation, adhesion, migration, and invasion of normal prostate epithelial cells (PNT1A). Improved survival in two- and three-dimensional cell cultures was noted as well as visual changes in colony size and structure in Geltrex™. Stimulatory influence on cell viability of each peptide applied single was lower than in combination. Enhanced survival of PNT1A cells appears to be associated with increased BCL2/BAX messenger RNA (mRNA) expression ratio. Modulation of cell spreading and cell-extracellular matrix adhesion dynamics were also altered as an influence of tested hormone application. However, long-term Ang II and RLN2 effects may lead to an increase of normal prostate cell migration and invasion abilities. Moreover, gelatin zymography revealed that both gelatinases A and B were augmented by Ang II treatment, whereas RLN2 significantly stimulated only MMP-9 secretion. These results support the hypothesis that deregulation of locally secreted peptide hormones such as Ang II and RLN2 may take part in the development of certain cancers, including prostate cancer. Moreover, the observed ability of relaxin 2 to act as a regulator of mRNA expression levels not only LGR7 but also classic angiotensin receptors suggested that renin-angiotensin system and relaxin family peptide system are functionally linked (AU)

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Plasma matrix metalloproteinase 9 as an early surrogate biomarker of advanced colorectal neoplasia / Metaloproteinasa 9 como biomarcador plasmático de neoplasia colorrectal avanzada

INTRODUCTION: Matrix metalloproteinases (MMPs) are overexpressed at different stages of colorectal carcinogenesis and could serve as early surrogate biomarkers of colorectal neoplasia. OBJECTIVE: To assess the utility of plasma MMP2 and MMP9 levels in the detection of advanced colorectal neoplasia and their correlation with tissue levels. METHODS: We analysed blood and tissue samples from patients with non-advanced adenomas (n = 25), advanced adenomas (n = 25), colorectal cancer (n = 25) and healthy controls (n = 75). Plasma and tissue gelatinase levels were determined by Luminex XMAP technology and gelatin zymography. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimum cut-off for the detection of advanced colorectal neoplasia. RESULTS: Plasma MMP2 levels were similar between groups whatever the type of lesion. Plasma MMP9 levels were significantly higher in patients with neoplastic lesions than in healthy controls (median 292.3 ng/ml vs. 139.08 ng/ml, P < 0.001). MMP9 levels were also higher in colorectal cancer than in non-advanced adenomas (median 314.6 ng/ml vs. 274.3 ng/ml, P = 0.03). There was a significant correlation between plasma and tissue levels of MMP9 (r =0.5, P < 0.001). The plasma MMP9 cut-off range with the highest diagnostic accuracy was between 173 ng/ml and 204 ng/ml (AUC = 0.80 [95% CI: 0.72-0.86], P < 0.001; sensitivity, 80-86% and specificity, 57-67%). CONCLUSION: Plasma MMP9 could be a surrogate biomarker for the early detection of advanced colorectal neoplasia, although its diagnostic performance could be increased by combination with other biomarkers

INTRODUCCIÓN: Las metaloproteinasas (MMP) son proteínas que se sobreexpresan en diferentes etapas de la carcinogénesis colorrectal y podrían ser biomarcadores de neoplasia colorrectal. OBJETIVO: Evaluar la utilidad de MMP2 y MMP9 en plasma para detectar neoplasia colorrectal avanzada y su correlación con los niveles tisulares. MÉTODOS: Se analizaron muestras de sangre y tejido en pacientes con adenomas no avanzados (n = 25), adenomas avanzados (n = 25), cáncer colorrectal (n = determinaron mediante tecnología xMAP Luminex y zimografía con gelatina. Se utilizaron curvas ROC para calcular el punto de corte óptimo para neoplasia colorrectal avanzada. RESULTADOS: Los niveles de MMP2 fueron similares en las distintas lesiones. Los niveles de MMP9 fueron significativamente superiores en los pacientes con lesiones neoplásicas comparados con controles sanos (mediana de 292,3 ng/ml vs. 139,08 ng/ml; p < 0,001). Los niveles de MMP9 fueron más altos en los cánceres colorrectales que en adenomas no avanzados (mediana de 314,6 ng/ml vs. 274,3 ng/ml; p = 0,03). Se observó correlación entre los niveles plasmáticos y tisulares de MMP9 (r = 0,5; p < 0,001). El rango de MMP9 plasma con mayor precisión diagnóstica fue 173-204 ng/ml (AUC = 0,80 [IC 95%: 0,72-0,86], p < 0,001; sensibilidad 80-86% y especificidad 57-67%). CONCLUSIÓN: Los niveles en plasma de MMP9 podrían ser un biomarcador útil para detectar neoplasia colorrectal avanzada. La combinación con otros biomarcadores podría aumentar su rendimiento diagnóstico

Metaloproteinasas y leptina en conductores de vehículo de servicio público con síndrome metabólico en Armenia, Quindío / Metalloproteinases and leptin in vehicle drivers of public service with metabolic syndrome in Armenia, Quindío

OBJETIVO: Describir la relación entre la metaloproteinasa (MMP) 2, la MMP-9 y la leptina en conductores de vehículo de servicio público con síndrome metabólico en la ciudad de Armenia, Quindío. MÉTODOS: La leptina se midió con la técnica de ELISA de laboratorio Millipore y las metaloproteinasas con la técnica de ELISA de R&D Systems. RESULTADOS: Se identificaron 57 conductores con síndrome metabólico, sexo masculino, con edad promedio de 45,35 años, IMC de 29,81 y un perímetro abdominal de 105,75 cm. La presión arterial (PA) fue de 126,5/82,5 mmHg. La leptina se encontró en 24,6 ng/ml; la MMP-2 en 28,1 ng/ml y la MMP-9 en 7,5 ng/ml. La relación entre la leptina y el perímetro abdominal fue estadísticamente significativa (p < 0,001). La variación explicada (R2) del perímetro abdominal se explica en un 80,12% por las variables del estudio y tiene una relación estadísticamente significativa con el IMC (p < 0,001), la MMP-2 (p = 0,01), la edad (p = 0,01), la PAS (p < 0,001) y la PAD (p < 0,001). La R2 de la leptina se explica en un 69,56% por las variables del estudio y tiene una relación estadísticamente significativa con el IMC (p < 0,001), la MMP-2 (p = 0,05) y los triglicéridos (p = 0,02). La R2 de la MMP-2 se explica en un 41,82% por las variables del estudio y tiene una relación estadísticamente significativa con el perímetro abdominal (p = 0,01), la glucemia (p = 0,01) y la edad (p = 0,03). CONCLUSIONES: Se encontraron relaciones estadísticamente significativas entre el perímetro abdominal con la MMP-2; de la leptina con la MMP-2, y de la MMP-2 con el perímetro abdominal y la glucemia

OBJECTIVE: To describe the relationship between metalloproteinase (MMP) 2, MMP-9, and leptin in drivers of public service vehicles with metabolic syndrome in the city of Armenia (Quindio, Colombia). METHODS: Leptin was measured using Millipore ELISA kits. MMP-2 and MMP-9 were measured with ELISA kits from R&D Systems. RESULTS: Fifty-seven male drivers with metabolic syndrome with a mean age of 45.35 years, BMI of 29.81, and an abdominal circumference of 105.75 cm were identified. Blood pressure values were 126.5/82.5 mmHg. Leptin, MMP-2, and MMP-9 levels were 24.6 ng/mL, 28,1 ng/mL, and 7.5 ng/mL respectively. The relationship between leptin and waist circumference was statistically significant (P < .001). The explained variation (R2) in waist circumference, is explained in a 80.12% for the study variables, has a statistically significant association with BMI (P < .001), MMP-2 (P = .01), age (P = .01), SBP (P < .001) and DBP (P < .001). The R2 of leptin, is explained in a 69.56% for the study variables, has a statistically significant association with BMI (P < .001), MMP-2 (P = .05) and triglycerides (P = .02). The R2 of MMP-2, explained in 41.82% of the study variables and has a statistically significant association with waist circumference (P = .01), glucose (P = .01) and age (P = .03). CONCLUSIONS: Statistically significant associations were found between waist circumference and MMP-2; leptin and MMP-2, and MMP-2 and waist circumference and blood glucose

Consideraciones clínicas de la expresión de P504S y metaloproteinasa de matriz 2 en células prostáticas circulantes en sangre diseminadas como resultado de una biopsia prostática trans-rectal guiada por ecografía / Expression of P504S and matrix metalloproteinase-2 in circulating prostate cells disseminated as a result of transrectal ultrasound guided biopsy as determined by immunocytochemistry: Clinical implications

OBJETIVO: la manipulación quirúrgica del cáncer tiene la potencialidad de aumentar la diseminación de células cancerosas al torrente sanguíneo y con esto el riesgo de metástasis. Presentamos el efecto de la biopsia prostática en la diseminación de estas células así como sus características fenotípicas. MÉTODOS: Se incluyeron cincuenta hombres que fueron sometidos a una biopsia prostática trans rectal como sospecha de cáncer de próstata en nuestro estudio. Se recolectaron muestras sanguíneas inmediatamente antes de la biopsia, una hora y 24 horas posterior a la misma, para detección de células prostáticas en sangre (CPC) así como para determinar sus características fenotípicas utilizando inmunocitoquímica estándar con anti PSA y luego caracterizarlas utilizando anti P504S y anti matriz de metaloproteinasa 2 (MMP-2). RESULTADOS: Catorce hombres (28%) tuvieron cáncer de próstata en la biopsia, 13 de estos fueron P504S + y MMP-2 + previo a la biopsia. Una hora posterior a la biopsia existió una mezcla de P504S + y P504S - así como de MMP2 + y MMP2 - en pacientes con biopsia positiva para cáncer, niveles que se igualaron a los pre biopsia luego de 24 horas. En pacientes negativos para cáncer, se detectaron células circulantes P504S - y MMP-2 -, algunas de ellas se mantuvieron por más de 24 horas. CONCLUSIONES: La biopsia prostática puede causar diseminación de células prostáticas malignas y benignas a la circulación y la mayoría son eliminadas dentro de las primeras 24 horas. No existió conversión de pacientes con cáncer de CPCs negativos a positivos lo que sugiere que la capacidad inherente de las células prostáticas de diseminar es más importante que el efecto de la biopsia prostática

OBJECTIVES: Surgical manipulation of cancer has been shown to increase blood borne cancer cell dissemination and increase the risk of metastasis. We present the effect of prostate biopsy on prostate cell dissemination and the phenotypic characteristics of these cells. METHODS: 50 men undergoing initial prostate biopsy for suspicion of prostate cancer were studied. Blood samples were taken immediately before, and 1 and 24 hours after biopsy for circulating prostate cells (CPC) determination and phenotypic characterization. CPCs were detected and counted using standard immunocytochemistry using anti-PSA and then characterized using anti-P504S and anti-matrix metalloproteinase-2 (MMP-2). RESULTS: 14 (28%) men had cancer detected on biopsy. 13/14 had P504S (+) and MMP-2 (+) cells detected prior to biopsy. One hour after biopsy there was a mixture of P504S (+) and P504S (-) cells detected, as well as MMP-2 (+) and MMP-2 (-) cells detected. 24 hours after biopsy the same 13/14 men remained positive, although the number of CPCs increased 1 hour after biopsy and then the numbers decreased to prebiopsy levels after 24 hours. In cancer negative men, P504S (-) and MMP-2 (-) cells were detected, some of these cells persisted 24 hours after biopsy. CONCLUSIONS: Prostate biopsy causes dissemination of prostate cells into the circulation, both malignant and benign; the majority of them are cleared within 24 hours. There was no conversion of negative to positive result in men with cancer, this suggests that the inherent capacity of malignant CPCs to disseminate is more important than the effect of dissemination caused by prostate biopsy

Matrix metallopeptidase 2 (MMP2) media la eliminación de MHC class I polypeptide-related sequence A (MICA) en el cáncer de células renales / Matrix metallopeptidase 2 (MMP2) mediates MHC class I polypeptide-related sequence A (MICA) shedding in renal cell carcinoma

Introducción: La molécula A relacionada con la cadena de clase i del CMH (MICA) es un ligando del grupo 2 de células asesinas naturales, y miembro D (NKG2D) de la activación de inmunorreceptores. La unión de la superficie de la célula tumoral MICA con NKG2D estimula las células asesinas (NK) y la inmunidad de las células T antitumorales. La eliminación de MICA por las células tumorales facilita la evasión inmune del tumor, lo cual podría contribuir en parte a la progresión tumoral. Materiales y métodos: Se aplicó inmunohistoquímica tanto en tejidos renales normales como neoplásicos. Se transfectaron las líneas de células tumorales de riñón humano 786-O y ACHIN, y se establecieron secuencias objetivo para silenciar la MMP2 humana a través de la expresión ARNhc. Se midió el grado de eliminación de MICA y se llevó a cabo una PCR cuantitativa en tiempo real, así como el análisis de Western blot. Resultados: La membrana de tipo metaloproteinasa de matriz-2 (MMP2) media en la eliminación de MICA, que se bloquea por la supresión de la expresión de MMP2. Simultáneamente, la sobreexpresión de MMP2 aumenta la eliminación de MICA, lo cual indica que MMP2 interviene en la liberación proteolítica de MICA soluble (sMICA) asociada al carcinoma de células renales, que facilita el escape tumoral inmune. Conclusiones: Dichos resultados sugieren que MMP2 podría ser un nuevo objetivo potencial para la terapia inmune de tumores. Un esclarecimiento de los mecanismos por los que los tumores eliminan MICA podría ser de gran importancia para el tratamiento del cáncer, para así reforzar las NK y la inmunidad antitumoral de las células T

Introduction: The MHC class i chain-related molecule A (MICA) is a ligand for the natural killer group 2, member D (NKG2D) immunoreceptor activation. The engagement of tumor cell surface MICA to NKG2D stimulates the NK and T cell antitumor immunity. Shedding of MICA by tumor cells facilitates tumor immune evasion, which might partially contribute to tumor progression. Material and methods: Inmunohistochemistry was performed on both normal and neoplastic renal tissue. Human renal carcinoma cell lines 786-0 and ACHIN were transfected and target sequences to silence human MMP2 by shRNA expression were established. The degree of MICA shedding was measured and quantitative real-time PCR and Western-blot analysis were performed. Results: The membrane type matrix metalloproteinase 2 (MMP2) mediated the MICA shedding, which was blocked by suppression of MMP2 expression. Concomitantly, MMP2 over-expression enhanced the MICA shedding, indicating that MMP2 was involved in the renal cell carcinoma associated proteolytic release of soluble MICA (sMICA), which facilitated the tumor immuneescape .Conclusions: These findings suggested that MMP2 might be a new potential target for tumor immune therapy. Elucidation of the mechanisms by which tumors shed MICA could be of a great importance for cancer treatment in order to reinforce the NK and T cell antitumor immunity

Diagnóstico de la insuficiencia cardíaca aguda y relevancia de los biomarcadores en pacientes de edad avanzada / Diagnosis of acute heart failure and relevance of biomarkers in elderly patients

El diagnóstico de insuficiencia cardíaca (IC) aguda es difícil en pacientes de edad avanzada con múltiples comorbilidades. Las escalas y criterios de clasificación basados exclusivamente en manifestaciones clínicas, como los de Framingham, carecen de especificidad suficiente. Además de la clínica, el diagnóstico debe estar basado en otros 2 pilares: los péptidos natriuréticos y el ecocardiograma. Ante una sospecha clínica baja, la normalidad de los péptidos natriuréticos descarta la IC aguda. En aquellos con sospecha clínica consistente debe realizarse también un ecocardiograma. El diagnóstico de IC con fracción de eyección preservada (ICFEP) requiere la detección de una aurícula izquierda aumentada de tamaño o la presencia de parámetros de disfunción diastólica. La elevación de los biomarcadores cardíacos parece responder al daño del miocardio y a los mecanismos de compensación que tiene el organismo frente a este (respuesta hormonal, inflamatoria y mecanismos de reparación). En la clínica la elevación de los marcadores de daño cardíaco (troponinas y péptidos natriuréticos) ha demostrado utilidad tanto en el diagnóstico de la IC aguda como en su pronóstico. El MMP-2 podría ser útil en el diagnóstico de ICFEP. Además del valor diagnóstico, otros biomarcadores son de ayuda en el pronóstico en la fase aguda de IC, como los de fallo renal (eGFR, cistatina y urea), los de inflamación (citocinas y proteína C reactiva [PCR]) y el marcador de regeneración celular galectina-3. Una idea prometedora en estudio es el uso de combinaciones de biomarcadores para predecir de una forma más precisa tanto el diagnóstico como el pronóstico de la IC aguda (AU)

Diagnosis of acute heart failure (HF) is difficult in elderly patients with multiple comorbidities. Risk scales and classification criteria based exclusively on clinical manifestations, such as the Framingham scales, lack sufficient specificity. In addition to clinical manifestations, diagnosis should be based on two key factors: natriuretic peptides and echocardiographic study. When there is clinical suspicion of acute HF, a normal natriuretic peptide level will rule out this process. When a consistent clinical suspicion is present, an echocardiographic study should also be performed. Diagnosis of HF with preserved ejection fraction (HF/pEF) requires detection of an enlarged left atrium or the presence of parameters of diastolic dysfunction. Elevation of cardiac biomarkers seems to be due to myocardial injury and the compensatory mechanisms of the body against this injury (hormone and inflammatory response and repair mechanisms). Elevation of markers of cardiac damage (troponins and natriuretic peptides) have been shown to be useful both in the diagnosis of acute HF and in prediction of outcome. MMP-2 could be useful in the diagnosis of HF/pEF. In addition to biomarkers with diagnostic value, other biomarkers are helpful in prognosis in the acute phase of HF, such as biomarkers of renal failure (eGFR, cystatin and urea), inflammation (cytokines and CRP), and the cell regeneration marker, galectin-3. A promising idea that is under investigation is the use of panels of biomarkers, which could allow more accurate diagnosis and prognosis of acute HF (AU)

El papel de la metaloproteinasa de la matriz MMP-9 y del inhibidor tisular de metaloproteinasa TIMP-2 como marcadores séricos de cáncer vesical / The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinasas as serum markers of bladder cancer

Introducción: El diagnóstico y la estadificación molecular del cáncer vesical basados en la detección de ARNm de gelatinasas (MMP-2 y MMP-9) en células circulantes y mononucleares de sangre periférica han mostrado resultados prometedores. Analizamos si la determinación de los correspondientes productos de síntesis proteica permite diagnosticar y caracterizar pacientes con neoplasia vesical. Material y método: Se ha llevado a cabo la cuantificación de los niveles séricos de MMP-2, MMP-9 y TIMP-2 en una serie de 42 individuos (31 pacientes con cáncer vesical en diversos estadios y 11 controles sanos) mediante técnica de ELISA. Se compararon las determinaciones entre casos y controles (U Mann-Whitney), así como entre diferentes grupos de tumores (U Mann-Whitney o Kruskal-Wallis), según las características clínico-patológicas (edad, sexo, categoría T, categoría M o grado). Se evaluó el rendimiento diagnóstico de estos marcadores mediante análisis de curvas ROC Resultados: Existe correlación entre las determinaciones de MMP-2 y TIMP-2 (R = 0,699; p > 0,0001) y de MMP-9 y TIMP-2 (R = 0,305; p = 0,049). Los pacientes con cáncer de vejiga presentan niveles más elevados de MMP-9 (p < 0,0001) y TIMP-2 (p = 0,047) que los controles. Así mismo, el cociente MMP-9/TIMP-2 también es superior en pacientes con cáncer (p < 0,001). No se detectan diferencias entre cáncer y control respecto a edad (p = 0,64) o sexo (p = 0,64). Tampoco se detectan diferencias con respecto a MMP-2 (p = 0,35) ni al cociente MMP-2/TIMP-2 (p = 0,45). Dentro de la población de pacientes con cáncer los valores de MMP-2 y MMP-9 difieren según categoría T (p = 0,022 y p = 0,038, respectivamente) y los de TIMP-2 según categoría M (p = 0,036). El análisis de curvas ROC mostró que tanto MMP-9 como el cociente MMP-9/TIMP-2 discriminan pacientes con cáncer y controles, con equivalente exactitud diagnóstica (ABC 0,953) y unos puntos de corte de 3,93 ng/ml (S 90%; E 81%) y de 0,053 ng/ml (S 96%; E 84%), respectivamente. Conclusiones: Los resultados obtenidos sugieren que tanto MMP-9 como TIMP-2 séricos podrían tener una aplicación en la predicción del desarrollo y progresión del cáncer vesical, y potencial utilidad como marcadores clínicos de la enfermedad. Se requieren estudios multicéntricos prospectivos que confirmen estos resultados preliminares (AU)

Introduction: The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer. Material and method: Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical-pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves. Results: There is a correlation between the determinations of MMP-2 and TIMP-2 (R = 0.699; P > 0.0001) and MMP-9 and TIMP-2 (R = 0.305; P = 0.049). Patients with bladder cancer have higher levels of MMP-9 (p < 0.0001) and TIMP-2 (P = 0.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P < 0.001). Differences were not detected between cancer and controls regarding age (P = 0.64) or gender (P = 0.64). Differences were also not detected regarding MMP-2 (P = 0.35) or MMP-2/TIMP-2 rate (P = 0.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P =0 .022 and P = 0.038, respectively) and those of the TIMP-2 according to M category (P = 0.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively. Conclusions: The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary (AU)

As metaloproteinases -2 e -9 da matrize o carcinoma espinocelular: uma análiseda literatura / Matrix metalloproteinase-2 and -9 and the squamous cell carcinoma: a literatura analyses

O Carcinoma espinocelular (CEC) trata-se de uma neoplasia maligna com potencial invasivo e inclusive metastático, sendo que vários fatores contribuempara esta invasividade local, dentre os quais estão as metaloproteinases da matriz (MMPs). Estas consistem em enzimas proteolíticas, que alémde exercerem funções fisiológicas, como a embriogênese, degradação e remodelação dos componentes da matriz extracelular (MEC), também participamdos processos de invasão e metástase. Nesta regulação agem também os inibidores teciduais das MMP (TIMPs) que atuam na inibição e controledestas enzimas.Existem pelo menos 21 subtipos de MMPs, sendo as metaloproteinases 2 e 9 (também chamadas gelatinases A e B, respectivamente) as principaisenzimas deste grupo estudadas neste processo.Novos estudos devem ser publicados a respeito do assunto, uma vez que a compreensão da carcinogênese é essencial para o desenvolvimento de tratamentosfuturo (AU)

The Squamous cell carcinoma (SCC) is a malignant cancer with metastatic potential; several factors contribute to its local invasiveness, among whichare the matrix metalloproteinases (MMPs).These consist of proteolytic enzymes, which in addition to exerting physiological functions, such as embryogenesis, degradation, and remodeling ofcomponents of the extracellular matrix, are also part of the process of invasion and metastasis. In this regulation, tissue inhibitors (TIMPs) also act inthe inhibition and control of these enzymes.There are at least 21 subtypes of MMPs, metalloproteinase 2 and 9 (also known as gelatinizes A and B respectively) are the main enzymes of the groupstudied in this process.Since the understanding of the carcinogenesis is essential for the development of future treatments, further studies should be published about thesubject (AU)

Análisis de la presencia de TGF-Beta1, BMP-7, MMP-2 y PEDF en distintas matrices óseas desmineralizadas / Analysis of TGF-Beta1, BMP-7, MMP-2 and PEDF presence in different demineralized bone matrices

Objetivo: Estudiar las proteínas de la matriz ósea desmineralizada, obtenidas de distintos donantes humanos y zonas óseas. Material y métodos: Se utilizaron matrices óseas desmineralizadas procedentes de hueso esponjoso granulado, cortical con esponjoso, cortical de tibia, cortical de fémur, cortical de peroné y de hueso esponjoso fragmentado. Se realizó un extracto de proteínas totales que fueron analizadas mediante western blot del factor de crecimiento transformante o TGF-Beta1, la proteína morfogénica ósea BMP-7, la metaloproteasa MMP-2 y el factor antiangiogénico PEDF (factor derivado del epitelio pigmentado). Resultados: Todas las matrices óseas resultaron positivas para la presencia de las 4 proteínas estudiadas, no obstante los niveles de éstas resultaron diferentes en las matrices empleadas. La matriz de hueso cortical presentó menor cantidad de TGF-Beta1, BMP-7 y PEDF. Conclusión: La presencia de proteínas inhibidoras (PEDF) o que favorecen la angiogénesis (MMP-2), apoya la hipótesis de la participación del proceso de formación de vasos en la osteoinducción por parte de este tipo de matrices. Así mismo, el tipo de matriz puede ser determinante en la inducción de la reparación de defectos óseos utilizando matrices óseas desmineralizadas

Aim: To study the osteoinduction capacity of different demineralized bone matrices obtained from different human bone fragments. Material and methods: Demineralized bone matrices obtained from trabecular granulated bone, trabecular and cortical bone, cortical bone from tibia, cortical bone from femur, cortical bone from fibula, and chips from trabecular bone, were used. We performed a total protein extract by digesting the matrix with collagenase, and used it in western blot experiments to analyze the presence of transforming growth factor TGF-Beta1, bone morphogenetic protein BMP-7, metaloproteinase MMP-2 and antiangiogenic factor PEDF or Pigment epithelium-derived factor. Results: All bone matrices were positive for the presence of the 4 proteins studied, nevertheless, the level of these proteins was different in the matrices employed. Conclusion: The presence of proteins that inhibit (PEDF) or facilitate (MMP-2) angiogenesis supports the participation of the process of new vessel formation in the osteoinduction exerted by these kind of matrices. In addition, the type of matrix may be a key factor in the repairing of bone defects using demineralized bone matrices

Metaloproteinasas y cáncer vesical: estado actual / Metaloproteinases and bladder cancer: state of the art

Durante los últimos diez años el papel de las metaloproteinasas en el desarrollo tumoral haalcanzado una importante relevancia. El descubrimiento de nuevas metaloproteinasas ha demostrado, no sólo su implicación en la disrupción de la matriz extracellular y la consecuente diseminación tumoral sino que diversos estudios han desvelado su papel en procesos deiniciación, promoción tumoral y apoptosis.Recientes trabajos desvelan también la relación entre niveles elevados de ciertas metaloproteinasas y sus inhibidores, sobre todo MMP2, MMP9, 17MPl Y 17MP2 en tejidoparafinado, orina y suero de pacientes con carcinoma vesical con características clínicopatológicasdesfavorables en cuanto a estadio y grado, por lo que en un futuro podríanconvertirse en buenas predictoras del comportamiento del cáncer vesical

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Las metaloproteasas como dianas terapéuticas en enfermedades reumatológicas / No disponible

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Correlación entre la expresión de citocinas proinflamatorias y metaloproteinasas de matriz en la fase aguda del ictus isquémico / Correlation between the expression of proinflammatory cytokines and matrix metalloproteinases in the acute phase of an ischemic stroke

Introducción. Las citocinas proinflamatorias son las principales responsables de la puesta en marcha de la cascada inflamatoria postisquémica. Recientemente se ha demostrado el papel deletéreo de las metaloproteinasas de matriz (MMP) en la fase aguda del ictus. En modelos animales se ha sugerido la existencia de una conexión entre la activación de ambas familias. Objetivo. Valorar si existe relación entre la expresión de MMP y la de citocinas proinflamatorias en la fase aguda del ictus isquémico en humanos. Pacientes y métodos. De todos los pacientes con ictus atendidos de forma consecutiva en un período de 10 meses, seleccionamos aquellos ictus de etiología cardioembólica que afectaban el territorio de la arteria cerebral media. Se determinaron de forma seriada MMP-9, MMP-2 e IL-6, mediante técnicas de ELISA, a la llegada del paciente a urgencias y a las 12, 24 y 48 horas del inicio de los síntomas. Resultados. Se estudiaron en total 39 pacientes. Se encontró una correlación positiva entre la expresión media de ambas MMP y la de IL-6 (r= 0,33, p= 0,040 para MMP-2 y r= 0,45, p= 0,004 para MMP-9). De los distintos tiempos estudiados, la mejor correlación fue la de MMP-9 con IL-6 a las 24 horas (r= 0,418, p= 0,010). A las 24 h se registró un pico de expresión de IL-6. Se evidenció una tendencia a que los valores basales de MMP-2 y MMP-9 se correlacionaran con el pico de IL-6 (r= 0,329, p= 0,061 para MMP-2 y r= 0,325, p= 0,061 para MMP9). Conclusión. Existe una relación entre la expresión de MMP y los fenómenos inflamatorios que ocurren durante la fase aguda del ictus isquémico (AU)