Clara L. Sampieri

The regulation of matrix metalloproteinases and their inhibitors

The matrix metalloproteinases (MMP) are a family of 23 enzymes in man. These enzymes were originally described as cleaving extracellular matrix (ECM) substrates with a predominant role in ECM homeostasis, but it is now clear that they have much wider functionality. Control over MMP and/or tissue inhibitor of metalloproteinases (TIMP) activity in vivo occurs at different levels and involves factors such as regulation of gene expression, activation of zymogens and inhibition of active enzymes by specific inhibitors. Whilst these enzymes and inhibitors have clear roles in physiological tissue turnover and homeostasis, if control of their expression or activity is lost, they contribute to a number of pathologies including e.g. cancer, arthritis and cardiovascular disease. The expression of many MMPs and TIMPs is regulated at the level of transcription by a variety of growth factors, cytokines and chemokines, though post-transcriptional pathways may contribute to this regulation in specific cases. The contribution of epigenetic modifications has also been uncovered in recent years. The promoter regions of many of these genes have been, at least partly, characterised including the role of identified single nucleotide polymorphisms. This article aims to review current knowledge across these gene families and use a bioinformatic approach to fill the gaps where no functional data are available.

Expression analysis of the entire MMP and TIMP gene families during mouse tissue development

Matrix metalloproteinases (MMPs) and adamalysins (ADAMs) cleave many extracellular proteins, including matrix, growth factors, and receptors. We profiled the RNA levels of every MMP, several ADAMs, and inhibitors of metalloproteinases (TIMPs and RECK) in numerous mouse tissues during development and in the uterus during pregnancy. Observations include: most secreted MMPs are expressed at low to undetectable levels in tissues, whereas membrane‐bound MMPs, ADAMs and inhibitors are abundant; almost every proteinase and inhibitor is present in the uterus or placenta at some time during gestation; the mouse collagenases mColA and mColB are found exclusively in the uterus and testis; and each tissue has its unique signature of proteinase and inhibitor expression.

Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-β1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-β1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-β1–induced TIMP3 expression. TGF-β1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-β1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-β1–induced TIMP3 may be an important mediator in lung fibrogenesis.

Matrix metalloproteinases and their tissue inhibitors in gastric cancer as molecular markers.

Gastric cancer is a complex disease that involves a range of biological individuals and tumors with histopathological features. The pathogenesis of this disease is multi-factorial and includes the interaction of genetic predisposition with environmental factors. Gastric cancer is normally diagnosed in advanced stages where there are few alternatives to offer and the prognosis is difficult to establish. Metastasis is the leading cause of cancer deaths. Identification of key genes and signaling pathways involved in metastasis and recurrence could predict these events and thereby identify therapeutic targets. In this context, the extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) represent a potential prognostic tool, because both genetic families regulate growth, angiogenesis, invasion, immune response, epithelial mesenchymal transition and cellular survival. Proteolytic parameters based on MMP/TIMP expression could be useful in the identification of patients with a high probability of developing distant metastases or peritoneal dissemination for each degree of histological malignancy. It is also probable that these parameters can allow improvement in the extent of surgery and dictate the most suitable therapy. We reviewed papers focused on human gastric epithelial cancer as a model and focus on the potential use of MMPs and TIMPs as molecular markers; also we include literature regarding gastric cancer risk factors, classification systems and MMP/TIMP regulation.

Differential effects of histone deacetylase inhibitors on phorbol ester‐ and TGF‐β1 induced murine tissue inhibitor of metalloproteinases‐1 gene expression

Expression of the tissue inhibitor of metalloproteinases‐1 (Timp‐1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor β1 (TGF‐β1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF‐β1 stimulation of Timp‐1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA‐induced Timp‐1 expression but repress TGF‐β1‐induced Timp‐1 expression. The repression of TGF‐β1‐induced Timp‐1 by TSA was maximal at 5 ng·mL−1, while for the superinduction of PMA‐induced Timp‐1 expression, the maximal dose is > 500 ng·mL−1 TSA. A further HDACi, valproic acid, did not block TGF‐β1‐induced Timp‐1 expression, demonstrating that different HDACs impact on the induction of Timp‐1. For either PMA or TGF‐β1 to induce Timp‐1 expression, new protein synthesis is required, and the induction of AP‐1 factors closely precedes that of Timp‐1. The effects of the HDACi can be reiterated in transient transfection using Timp‐1 promoter constructs. Mutation or deletion of the AP‐1 motif (−59/−53) in the Timp‐1 promoter diminishes PMA‐induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c‐Jun–/– cells, PMA still stimulates Timp‐1 expression, but TSA superinduction is lost. Transfection of a series of Timp‐1 promoter constructs identified three regions through which TSA superinduces PMA‐induced Timp‐1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v‐ets) oncogene homologue (Ets) or Sp1 binding motif.

Gastric cancer research in Mexico: A public health priority

This study aimed review studies conducted on Mexican patients diagnosed with gastric cancer and/or diseases associated with its development, in which at least one Mexican institute has participated, and to assess their contributions to the primary and secondary prevention of this disease. A search of the Medline database was conducted using the following keywords: gastric/stomach cancer, Mexico. Studies of the Mexican population were selected in which at least one Mexican Institute had participated and where the findings could support public policy proposals directed towards the primary or secondary prevention of gastric cancer. Of the 148 studies found in the Medline database, 100 were discarded and 48 were reviewed. According to the analysis presented, these studies were classified as: epidemiology of gastric cancer (5/48); risk factors and protectors relating to gastric cancer (9/48); relationship between Helicobacter pylori and pathologies associated with gastric cancer and the development of the disease (16/48); relationship between the Epstein-Barr virus and pathologies associated with gastric cancer and the development of the disease (3/48); molecular markers for the development of diseases associated with gastric cancer and gastric cancer (15/48). Mexico requires a program for the prevention and control of gastric cancer based on national health indicators. This should be produced by a multidisciplinary committee of experts who can propose actions that are relevant in the current national context. The few studies of gastric cancer conducted on the Mexican population in national institutes highlight the poor connection that currently exists between the scientific community and the health sector in terms of resolving this health issue. Public policies for health research should support projects with findings that can be translated into benefits for the population. This review serves to identify national research groups studying gastric cancer in the Mexican population.

Metaloproteasas de la matriz extracelular como marcadores moleculares en cáncer gástrico

Gastric cancer is the second leading cause of cancer-associated mortality in the world. Prognosis in patients with gastric cancer is difficult to establish because it is commonly diagnosed when gastric wall invasion and metastasis have occurred. Currently, some members of the extracellular matrix metalloproteinases have been identified, whose expression in gastric tumor tissue is significantly elevated compared to healthy gastric tissue. Matrix metalloproteinases are 24 zinc-dependent endopeptidases that catalyze the proteolysis of the extracellular matrix. This degradation allows the cancer cells invade the surrounding stroma and trigger metastasis. Upregulation of certain matrix metalloproteinases in gastric cancer has been associated with a poor prognosis and elevated invasive capacity. This review compiles evidence about the genetic expression of matrix metalloproteinases in gastric cancer and their role in tumour invasion and metastasis, emphasizing their potential as molecular markers of prognosis.

Expression of the Matrix Metalloproteases 2, 14, 24, and 25 and Tissue Inhibitor 3 as Potential Molecular Markers in Advanced Human Gastric Cancer

Background. During progression of gastric cancer (GC), degradation of the extracellular matrix is mediated by the matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs): changes in the expression of these have been related to unfavorable prognosis in GC. Objective. To analyze the expression of certain MMPs and TIMPs in chronic superficial gastritis (SG) and GC. Methods. The expression of MMPs and TIMPs was determined using qRT-PCR; the expression was classified, using threshold cycle (C T) values, as very high (C T ≤ 25), high (C T = 26–30), moderate (C T = 31–35), low (C T = 36–39), or not detected (C T = 40). Strength of association was estimated between the proteins, which were detected by Western blot, and the risk of developing GC. Results. We found a high expression of MMP1, MMP2, MMP14, TIMP1, and TIMP3; moderate one of MMP9 and MMP25, and low one of MMP13 and MMP24 in both tissues. In absolute mRNA levels, significant differences were found in expression of MMP2, MMP24, and MMP25, which are overexpressed in GC compared with SG. The presence of the proteins MMP-14 and TIMP-3 was associated with the risk of developing GC. Conclusions. We consider that MMP2, MMP24, and MMP25 and the proteins MMP-14 and TIMP-3 could be candidates for prognostic molecular markers in GC.

RevisiónMetaloproteasas de la matriz extracelular como marcadores moleculares en cáncer gástricoMatrix metalloproteases as molecular markers in gastric cancer

Gastric cancer is the second leading cause of cancer-associated mortality in the world. Prognosis in patients with gastric cancer is difficult to establish because it is commonly diagnosed when gastric wall invasion and metastasis have occurred. Currently, some members of the extracellular matrix metalloproteinases have been identified, whose expression in gastric tumor tissue is significantly elevated compared to healthy gastric tissue. Matrix metalloproteinases are 24 zinc-dependent endopeptidases that catalyze the proteolysis of the extracellular matrix. This degradation allows the cancer cells invade the surrounding stroma and trigger metastasis. Upregulation of certain matrix metalloproteinases in gastric cancer has been associated with a poor prognosis and elevated invasive capacity. This review compiles evidence about the genetic expression of matrix metalloproteinases in gastric cancer and their role in tumour invasion and metastasis, emphasizing their potential as molecular markers of prognosis.

Viral coinfection in acute respiratory infection in Mexican children treated by the emergency service: A cross-sectional study

BackgroundAcute respiratory infections (ARIs) cause illness. Children under five years of age are highly vulnerable to these infections. Viral coinfection or multiple viral infection is a variable that can have a significant impact on the evolution of these diseases.MethodsThis cross-sectional study was carried out in Mexican children (under five years of age) who had an ARI and who were treated by an emergency service in a hospital in Guadalajara, Jalisco, Mexico. The viral etiology, as well as the presence of multiple viral infections, was determined. A structured questionnaire was used to obtain demographic and clinical information. Odds ratio (OR) was calculated, and univariate and multivariate analyses using logistic regression were performed.ResultsIn the study population, metapneumovirus (hMPV) was the most frequent virus (22%), followed by adenovirus (hAD) (16%), respiratory syncytial virus (RSV) (14%), rhinovirus (hRV) (12%), bocavirus (hBoV) (9%), influenza virus (IF) (7%), and parainfluenza (PIF) (4%). The frequency of viral coinfections was 31.62%, and multiple logistic regression analysis revealed that hMPV, RSV, PIF, and hBoV were independently associated with multiple viral infection. No difference was found in the clinical manifestation of children with simple and multiple infections. Simple hMPV infection was associated with patients who presented with severe ARI. Using a multivariate analysis, we found that overcrowding is associated with coinfection when the viral etiology was hRV (OR = 2.56, 95% confidence interval (CI) 1.07 to 6.13), IF (OR = 2.56, 95% CI 1.07 to 6.13), PIF (OR = 2.96, 95% CI 1.15 to 7.65), hAD (OR = 2.56, 95% CI 1.07 to 6.13), and hBoV (OR = 2.9, 95% CI 1.14 to 7.34).ConclusionsViral coinfections are frequent in children requiring treatment by an emergency service. However, the severity of ARI is similar to that of children with a simple infection. The hMPV is common and may confer a significant disease burden in the Mexican population. Finally, overcrowding is a housing characteristic that favors the development of coinfections.