ABSTRACT
En las últimas décadas se ha avanzado en el conocimiento de la regulación del metabolismo del Hierro (Fe). La Hepcidina (Hp), producida por los hepatocitos, regula la absorción de hierro desde el tubo digestivo y la liberación desde los depósitos del sistema macrofágico y del hígado. En caso de deficiencia de Fe, la Hp está disminuida entregando Fe a la transferrina (Tf). El aumento de Fe y de las citoquinas de la inflamación estimulan la producción de Hp. El ejecutor de la Hp es la Ferroportina (FP), único exportador de Fe. Hay reguladores naturales de la Hp, como la Matriptasa 2. Las mutaciones que limitan su expresión inducen dificultades en la disponibilidad de Fe (IRIDA, sobrecarga de Fe). En los últimos años se ha identificado la Eritroferrona, producida por los eritroblastos activos en la eritropoyesis. Inhibe la síntesis de Hp, permitiendo la liberación del hierro de los depósitos y su absorción por el tubo digestivo, para facilitar la disponibilidad de Fe para la eritropoyesis. Aún no está definido cómo se podrán utilizar estos elementos en el campo diagnóstico, su estandarización y su aplicación terapéutica, pero es probable que resulten de gran utilidad.
In the last decades, a lot of progress has been made on the knowledge of iron (Fe) metabolism regulation. Hepcidin (Hp) is produced by hepatocytes and it regulates the iron absorption from the duodenum and the liberation from macrophages and from the liver. When there is iron deficiency, Hp, which delivers iron to transferrin (Tf), is low. Iron overload and inflammation cytokines stimulate Hp production. The Hp natural executor is Ferroportin (FP), which is the only iron exporter from the cells. One of the natural regulators of Hp is Matriptasa 2, which down regulates Hp. Mutations that limit their expression induce iron overload and anemia (IRIDA). In the last few years, Erythroferrone (ERFE) was discovered. ERFE is produced by active erythroblasts: it inhibits Hp synthesis, allowing the iron liberation from deposits and its duodenal absorption, and also the iron release from macrophages facilitating the erythroid production. The erythroblastic activity, even ineffective, acts as a stimulus of ERFE synthesis. Until now, it has not been defined yethow these different variables could be used for diagnosis, its standardization, or for therapeutic applications, but it is highly probable that they will improve our knowledge and managements kills in this field.
Nas últimas décadas háavanços no conhecimento da regulação do metabolismo do Ferro (Fe). A Hepcidina (Hp), produzida pelos hepatócitos, regula a absorção do ferro desde o tubo digestivo e a liberação desde os depósitos do sistema macrofágico e do fígado. Em caso de deficiência de Fe, a Hp está diminuída entregando Fe à transferrina (Tf). O aumento de Fe e as citoquinas da inflamação estimulam a produção de Hp. O executor da Hp é a Ferroportina (Fp), único exportador de Fe. Há reguladores naturais da Hp, como a Matriptase 2. As mutações que limitam sua expressão induzem dificultades na disponibilidade de Fe (IRIDA, sobrecarga de Fe). Nos últimos anos se identificou que a Eritroferrona, produzida pelos eritroblastosativos na eritropoiese inibe a síntese de Hp, permitindo a liberação de ferro dos depósitos e a absorção pelo tubo digestivo, para facilitar a disponibilidade de Fe para a eritropoiese. Ain da não sedefiniu como poderãoser utilizadosestes elementos no campo diagnóstico, sua padronização e sua aplicação terapêutica, mas é provável que sejam de grande utilidade.
Subject(s)
Humans , Iron Metabolism Disorders/diagnosis , Hepcidins , Iron/metabolism , Anemia , IronABSTRACT
El mantenimiento de la homeostasia del hierro es esencial para el funcionamiento fisiológico normal de los seres vivos. Recientemente se descubrió que la matriptasa 2, una serin proteasa transmembrana tipo II, también conocida por las siglas en inglés TMPRSS6, tiene una función esencial en la homeostasis de este mineral. Este hallazgo derivó inicialmente de la observación de que ratones con deficiencia de esta proteína presentaban anemia como consecuencia de la elevación de los niveles de hepcidina y la interrupción de la absorción intestinal de hierro. Los análisis posteriores in vitro demostraron que la matriptasa 2 suprime la vía de estimulación de la transcripción de la hepcidina que implica a la hemojuvelina como co-receptor. En concordancia con el patrón de anemia de los ratones mutantes, se encontró que el patrón de individuos con anemia por deficiencia de hierro resistente al hierro (en inglés IRIDA), era ocasionado por mutaciones del gen Tmprss6 que implican anulación de la actividad proteolítica de la enzima. En este trabajo se presentan aspectos relacionados con la identificación y caracterización de la matriptasa 2, así como su participación en el metabolismo del hierro.
The maintenance of iron homeostasis is essential for the normal physiological functioning of the living beings. Recently, it was discovered the Matriptase 2, a type II trans-membrane serine protease, also known by English acronyms TMPRSS6, having an essential function in homeostasis of this mineral. This finding initially derived from the observation that mice deficient of this protein had anemia as consequence of rise of hepcidine levels and the interruption of iron intestinal absorption. The in vitro later analyses showed that 2 Matriptase suppress the stimulation way of hepcidine transcription involving to hemojuvelin as a co-receptor. In agreement with the anemia pattern of mutant mice, we founded that pattern from subjects presenting with iron-deficiency anemia and iron-resistant (IRIDA) was created by Tmprsst gen mutations involving the elimination of enzymatic proteolytic activity. In present paper are showed the features related to identification and characterization of the 2 Matriptase, as well as, its involvement in iron metabolism.
ABSTRACT
OBJECTIVE: The purposes of this study were to examine the expression of matriptase, and its inhibitor, HAI-1, in epithelial ovarian cancer and to assign clinicopathological correlations and to discuss the matriptase/inhibitor (HAI-1) system in the context of ovarian cancer and to examine the possibility that this system might be a useful therapeutic target in this disease. METHODS: A retrospective study was performed in 51 patients with primary epithelial ovarian cancer staged over Ic who have been diagnosed and treated at Kyung Hee university medical center from Jan. 1991 to Mar. 2003. They were managed with cytoreductive surgery and chemotherapy. This study was performed in paraffin embedded blocks of primary epithelial ovarian cancer of 51 patients by means of immunohistochemistry. In addition, to validate protein expression data at the gene level, matriptase/HAI-1 mRNA expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) on frozen specimens from 10 ovarian cancers. Statistical analyses of immunohistochemistry (IHC) expression data with clinicopathological parameters and survival were then performed. RESULTS: Of 51 ovarian tumors tested, 25 (49%) and 37 (72.5%) were positive staining for matriptase and HAI-1 by IHC, respectively. Of 18 stage I/II tumors, 11 (61.1%) stained positive for matriptase, and 15 (83.3%) stained positive for HAI-1; Of 18 stage I/II tumors, 10 (55.6%) tumors showed coexpression. Of 33 stage III/IV tumors, 14 (42.4%) stained positive for matriptase and 22 (66.7%) stained positive for HAI-1; Of 33 stage III/IV tumors, 11 (33.3%) tumors showed coexpression. CONCLUSION: No relationship was found between the expression of either matriptase or HAI-1 with clinicopathological parameters and survival. However, stage I/II ovarian tumors are more likely to express matriptase and HAI-1 than are the more advanced disease stage III/IV tumors. Correspondingly, the low frequency of matriptase and HAI-1 coexpression is more likely to be associated with stage III/IV tumors than stage I/II tumors. Such an imbalance in the matriptase: HAI-1 ratio could promote the proteolytic activity of matriptase and, consequently, a more invasive phenotype in the advanced tumors.
Subject(s)
Humans , Academic Medical Centers , Drug Therapy , Immunohistochemistry , Ovarian Neoplasms , Paraffin , Phenotype , Retrospective Studies , RNA, Messenger , Serine Proteases , SerineABSTRACT
OBJECTIVE: Tumor-associated differentially expressed gene-15 (TADG-15/Matriptase/MT-SP1) is an epithelial-derived, integral serine protease which has been implicated in the progression of epithelial tumors. The aims of this study were to evaluate the expression pattern of TADG-15 in cervical squamous cell carcinoma and investigate the different expressions according to presence of lymph node metastasis. METHODS: Tumor specimens were obtained from each 20 patients with invasive squamous cell carcinoma (ISCC) with and without lymph node (LN) metastasis. Normal cervical tissues as control were obtained from 10 patients with myoma uteri. Immunohistochemical analysis was performed with antibody to TADG-15. RESULTS: The immunohistochemical staining showed that the expression of TADG-15 was undetectable in all normal squamous epithelia, but had variable staining in the basal layer of normal endocervical glands. The expression of TADG-15, exhibiting cytoplasmic and membranous staining, were significantly up-regulated in almost all (95%) of the ISCC in comparison to the normal control (P<0.001). But the expression of TADG-15 was not significantly different between ISCC with and ISCC without LN metastasis (P=0.56). However there was increasing tendency of expression in ISCC with LN metastasis in comparison to ISCC without LN metastasis. CONCLUSION: These results suggest that TADG-15 may play a significant role in carcinogenesis of squamous cell carcinoma of the uterine cervix and may represent novel markers for this disease. Further studies of serine protease and TADG-15 gene will likely result in the development of novel approaches for early detection and therapy of this disease.