The Role of the Metzincin Superfamily in Prostate Cancer Progression: A Systematic-Like Review.

Prostate cancer remains a leading cause of cancer-related morbidity in men. Potentially important regulators of prostate cancer progression are members of the metzincin superfamily of proteases, principally through their regulation of the extracellular matrix. It is therefore timely to review the role of the metzincin superfamily in prostate cancer and its progression to better understand their involvement in this disease. A systematic-like search strategy was conducted. Articles that investigated the roles of members of the metzincin superfamily and their key regulators in prostate cancer were included. The extracted articles were synthesized and data presented in tabular and narrative forms. Two hundred and five studies met the inclusion criteria. Of these, 138 investigated the role of the Matrix Metalloproteinase (MMP) subgroup, 34 the Membrane-Tethered Matrix Metalloproteinase (MT-MMP) subgroup, 22 the A Disintegrin and Metalloproteinase (ADAM) subgroup, 8 the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) subgroup and 53 the Tissue Inhibitor of Metalloproteinases (TIMP) family of regulators, noting that several studies investigated multiple family members. There was clear evidence that specific members of the metzincin superfamily are involved in prostate cancer progression, which can be either in a positive or negative manner. However, further understanding of their mechanisms of action and how they may be used as prognostic indicators or molecular targets is required.

Decreased ADAMTS-1, -9 and -20 levels in women with endometrial polyps: a possible link between extracellular matrix proteases and endometrial pathologies.

A disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs (ADAMTS) protein superfamily includes 19 secreted metalloproteases. Proteolytic substrates of ADAMTS enzymes have been linked to female reproductive function. Herein, we aimed to investigate serum ADAMTS-1, -9 and -20 levels in women with and without endometrial polyps (EPs). The study group (n = 40) consisted of women who had hysteroscopically detected and histologically confirmed EPs whereas control group (n = 40) was recruited from those women without any endometrial pathology. Data recorded for every woman were as follows: age, body mass index, gravidity and parity, number of miscarriages, smoking status and serum ADAMTS-1, -9 and -20 levels. ADAMTS-1, -9 and -20 values were measured by commercially available ELISA kits. No statistically significant differences between the groups were observed in terms of demographics. There were also no statistically significant differences between the groups with regard to ADAMTS-1 and -20 levels, although both of them were lower in the study group. However, ADAMTS-9 was significantly lower in the study group compared to the controls (p = .010). The optimal cut off value of ADAMTS-9 in predicting EPs was found to be 163.2 ng/mL with 100% sensitivity and 35% specificity. In conclusion, ADAMTS-9 protein is decreased in women with EPs. Impact statement What is already known on this subject? Endometrial polyps (EPs) are common and are generally benign gynaecologic disorders. ADAMTS enzymes comprise a zinc metalloproteinase gene family that has roles in vascular biology, inflammation and especially in the control of the function and structure of the extracellular matrix (ECM). ECM plays an important role in the pathogenesis of myomas, adenomyosis and abnormal uterine bleeding, as well as EPs. There is an interest in these proteases, especially with regard to the physiology of ovulation and implantation. They are also associated with carcinogenesis and metastasis. One of the most feared consequences of EPs is the risk of malignancy. Therefore, it is important in gynaecology practice to diagnose these endometrial abnormalities. What do the results of this study add? This is the first study performed to investigate the relationship between some ADAMTS (-1, -9 and -20) proteases and uterine polyps. Our results demonstrate novel molecular mediators contributing to EPs physiopathology. What are the implications of these findings for clinical practice and/or further research? ADAMTS-9 is defined as a tumour suppressor gene in various malignancies. Decreased ADAMTS-9 protein, which is the product of this gene, may have a role in the pathogenesis of EPs. There is a need for further research that should be done with benign-malign EPs.

Protective effects of alogliptin against TNF-α-induced degradation of extracellular matrix in human chondrocytes.

Osteoarthritis (OA) is a common debilitating disease most prevalent among the elderly population worldwide. Excessive degradation of the articular extracellular matrix is a pivotal event in the development of OA. Preventative treatments against the destruction of type II collagen and aggrecan, the two main components of the articular extracellular matrix, may serve as a novel therapy against the progression of OA. In the current study, we investigated whether the DPP-4 inhibitor alogliptin could prevent degradation of the articular extracellular matrix in human primary chondrocytes. Pretreatment with alogliptin successfully prevented degradation of type II collagen and aggrecan in a dose-dependent manner by reducing increased expression of MMP-1, -3, and -13 as well as ADAMTS-4 and -5 induced by treatment with TNF-α. Furthermore, pretreatment with alogliptin also reduced TNF-α-induced expression of IKKα/ß, IκBα and NF-κB in human primary chondrocytes. This suggests that DPP-4 inhibitors such as alogliptin may be used as an effective preventative therapy against continued destruction of the articular extracellular matrix in OA.

Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and its therapies. However, direct and accurate measurement of oxygen concentration and evaluation of hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions shown by measuring partial pressure of oxygen (pO2), the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia-inducible factor and neuroglobin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, sorafenib, 2-methoxyestradiol, and celastrol. This review focuses primarily on the results of clinical and animal studies.

Operatoria dental y endodoncia 1: la degradación de la interfaz resina-dentina favorece la filtración bacteriana / Operative dentistry and endodontics 1: the interface resin-dentin degradation allows for the bacterial microleakage

La integridad y la estabilidad de la interfase adhesivo/dentina en las restauraciones realizadas mediante resinas compuestas se encuentra constantemente comprometida por la hidrólisis progresiva de sus componentes hidrofílicos y la degradación de la matriz colágena, producida por la reactivación de una serie de endopeptidasas denominadas metaloproteinasas (MMP) y otras enzimas colagenolíticas que se encuentran fosilizadas en la matriz de la dentina. Esto lleva a la destrucción de la capa híbrida y facilita la penetración bacteriana en la interfase, el aumento de la hipersensibilidad posoperatoria y la formación de caries recurrentes. Estos problemas inciden además en la pérdida de retención de la restauración y se constituyen en el principal factor etiológico de los procesos inflamatorios que comprometen seriamente la salud de la pulpa dental. Debido a que la integridad de la matriz colágena es esencial para preservar la durabilidad de la adhesión de las restauraciones, se han intentado algunas estrategias, con el objeto de inhibir o al menos reducir en lo posible la acción de las enzimas colagenolíticas sobre la estabilidad de la interfase. A pesar de que algunas de las estrategias ensayadas hasta el momento han demostrado ser eficaces, aún se encuentran en una etapa netamente experimental y requieren ser más profundamente investigadas

Dominant contribution of the proteasome and metalloproteinases to TAP-independent MHC-I peptide repertoire.

Tumors frequently display defects in the MHC-I antigen processing machinery, such as deficiency of the peptide transporter TAP. Interestingly, the residual peptide repertoire contains neo-antigens which are not presented by processing-proficient cells. We termed these immunogenic peptides TEIPP ('T-cell epitopes associated with impaired peptide processing') and were interested to unravel their TAP-independent processing pathways. With an array of chemical inhibitors we assessed the participation of numerous proteases to TAP-independent peptides and found that the previously described catalytic enzymes signal peptidase and furin contributed in a cell-type and MHC-I allele-specific way. In addition, a dominant role for the proteasome and metallopeptidases was observed. These findings raised the question how these proteasome products get access to MHC-I molecules. A novel TEIPP peptide-epitope that represented this intracellular route revealed that the lysosomal peptide transporter ABCB9 ('TAP-like') was dispensable for its presentation. Interestingly, prevention of endolysosomal vesicle acidification by bafilomycin enhanced the surface display of this TEIPP peptide, suggesting that this proteasome-dependent pathway intersects endolysosomes and that these antigens are merely destroyed there. In conclusion, the proteasome has a surprisingly dominant role in shaping the TAP-independent MHC-I peptide repertoire and some of these antigens might be targeted to the endocytic vesicular pathway.

ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation.

ADAMTS-12 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which were known to play important roles in various biological and pathological processes, such as development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis. In this review, we briefly summarize the structural organization of ADAMTS-12; concentrate on the emerging role of ADAMTS-12 in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation; and end with the perspective research of ADAMTS-12 and its potential as a promising diagnostic and therapeutic target in various kinds of diseases and conditions.

Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative movement disorder; however, its etiology remains elusive. Nevertheless, in vivo observations have concluded that oxidative stress is one of the most common causes in the pathogenesis of Parkinson's disease. It is known that mitochondria play a crucial role in reactive oxygen species-mediated pathways, and several gene products that associate with mitochondrial function are the subject of Parkinson's disease research. The PTEN-induced kinase 1 (PINK1) protects cells from mitochondrial dysfunction and is linked to the autosomal recessive familial form of the disease. PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. Several proteins participate in mitochondrial networks, and they are associated with PINK1. The E3 ubiquitin ligase Parkin, the protease presenilin-associated rhomboid-like serine protease, the tyrosine kinase c-Abl, the protein kinase MARK2, the protease HtrA2, and the tumor necrosis factor receptor-associated protein 1 (TRAP1) provide different steps of control in protection against oxidative stress. Furthermore, environmental toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have been identified as contributors to parkinsonism by increasing oxidative stress in dopaminergic neurons. The present review discusses the mechanisms and effects of oxidative stress, the emerging concept of the impact of environmental toxins, and a possible neuroprotective role of the antioxidant astaxanthin in various neurodegenerative disorders with particular emphasis in Parkinson's disease.

Par1b induces asymmetric inheritance of plasma membrane domains via LGN-dependent mitotic spindle orientation in proliferating hepatocytes.

The development and maintenance of polarized epithelial tissue requires a tightly controlled orientation of mitotic cell division relative to the apical polarity axis. Hepatocytes display a unique polarized architecture. We demonstrate that mitotic hepatocytes asymmetrically segregate their apical plasma membrane domain to the nascent daughter cells. The non-polarized nascent daughter cell can form a de novo apical domain with its new neighbor. This asymmetric segregation of apical domains is facilitated by a geometrically distinct "apicolateral" subdomain of the lateral surface present in hepatocytes. The polarity protein partitioning-defective 1/microtubule-affinity regulating kinase 2 (Par1b/MARK2) translates this positional landmark to cortical polarity by promoting the apicolateral accumulation of Leu-Gly-Asn repeat-enriched protein (LGN) and the capture of nuclear mitotic apparatus protein (NuMA)-positive astral microtubules to orientate the mitotic spindle. Proliferating hepatocytes thus display an asymmetric inheritance of their apical domains via a mechanism that involves Par1b and LGN, which we postulate serves the unique tissue architecture of the developing liver parenchyma.

Pulmonary lymphangioleiomyomatosis: literature update.

Pulmonary lymphangioleiomyomatosis is an uncommon disease of unknown etiology characterized by the proliferation of abnormal smooth muscle cells in the lungs, leading to parenchymal destruction and progressive respiratory failure. The natural history of this disease remains poorly understood, primarily seen in women of childbearing age. The diagnosis can be difficult because symptoms are nonspecific and very similar to other respiratory diseases like asthma, emphysema and bronchitis. Lymphangioleiomyomatosis may not be diagnosed until a pneumothorax, chylothorax, interstitial lung disease or angiomyolipomas are discovered. The recent advances in genetic and molecular research provide new hope to discover the intricate mechanism of disease and evaluate new therapies. Internists, primary care physicians and pulmonologists should be aware of this condition in order to avoid delay in the diagnosis and institute appropriate therapy. The clinical features, pathophysiology, molecular genetics and medical treatment will be reviewed.

A functional and structural study of the major metalloprotease secreted by the pathogenic fungus Aspergillus fumigatus.

Fungalysins are secreted fungal peptidases with the ability to degrade the extracellular matrix proteins elastin and collagen and are thought to act as virulence factors in diseases caused by fungi. Fungalysins constitute a unique family among zinc-dependent peptidases that bears low sequence similarity to known bacterial peptidases of the thermolysin family. The crystal structure of the archetype of the fungalysin family, Aspergillus fumigatus metalloprotease (AfuMep), has been obtained for the first time. The 1.8 Šresolution structure of AfuMep corresponds to that of an autoproteolyzed proenzyme with separate polypeptide chains corresponding to the N-terminal prodomain in a binary complex with the C-terminal zinc-bound catalytic domain. The prodomain consists of a tandem of cystatin-like folds whose C-terminal end is buried into the active-site cleft of the catalytic domain. The catalytic domain harbouring the key catalytic zinc ion and its ligands, two histidines and one glutamic acid, undergoes a conspicuous rearrangement of its N-terminal end during maturation. One key positively charged amino-acid residue and the C-terminal disulfide bridge appear to contribute to its structural-functional properties. Thus, structural, biophysical and biochemical analysis were combined to provide a deeper comprehension of the underlying properties of A. fumigatus fungalysin, serving as a framework for the as yet poorly known metallopeptidases from pathogenic fungi.

Lower incidence of hepatic metastases of colorectal cancer in patients with chronic liver diseases: meta-analysis.

BACKGROUND/AIMS: The rarity of metastatic malignancy in injured liver has been noticed. This meta-analysis evaluates the difference in occurrence of metastatic colorectal cancer in healthy and chronically injured liver. METHODOLOGY: Literature search of occurrence of metastatic colorectal cancer in chronically injured liver opposed to healthy liver was conducted. Chronically injured/damaged liver included cirrhosis, steatosis or fatty liver and infection with Hepatitis virus B or C. RESULTS: A total of 7 retrospective studies between 1992 and 2010 matched the selection criteria with total of 4049 patients. Results suggest significantly lower incidence of colorectal metastasis in chronically injured liver (Pooled odds ratio = 0.260 (95% CI = 0.18 to 0.38); χ² (test odds ratio differs from 1) = 45.90 (df = 1); p <0.0001). CONCLUSIONS: Patients with chronic liver injury have significantly lower occurrence of hepatic metastasis of primary colorectal cancer than the patients with healthy liver.

[Role of metalloproteinases and their inhibitors in tumors]. / Rol de las metaloproteinasas y sus inhibidores en patología tumoral.

Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for future therapeutic strategies of this malignant disease.

Rol de las metaloproteinasas y sus inhibidores en patología tumoral / Role of metalloproteinases and their inhibitors in tumors

Las metaloproteinasas (MMPs) intervienen en diversos procesos fisiológicos y patológicos del organismo. Regulan, por ejemplo, las vías de señalización que controlan el crecimiento celular, la inflamación y la angiogénesis. Cumplen funciones moduladoras en el complejo microambiente tumoral interviniendo en las etapas tempranas de la carcinogénesis, en la invasión y la producción de metástasis tumorales. Participan en el procesamiento de moléculas bioactivas como citoquinas, quemoquinas y factores de crecimiento. Las MMPs tienen como substrato a las proteínas de la matriz extracelular (MEC) y su actividad es regulada por inhibidores endógenos (TIMPs). El adecuado balance entre ambas moléculas es fundamental para mantener la homeostasis. Debido al papel que desempeñan en diferentes etapas de la biología del cáncer, son un blanco potencial para futuras estrategias en la terapéutica de esta enfermedad.

Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for fu ture therapeutic strategies of this malignant disease.

Regulation of the transforming growth factor ß pathway by reversible ubiquitylation.

The transforming growth factor ß (TGFß) signalling pathway plays a central role during embryonic development and in adult tissue homeostasis. It regulates gene transcription through a signalling cascade from cell surface receptors to intracellular SMAD transcription factors and their nuclear cofactors. The extent, duration and potency of signalling in response to TGFß cytokines are intricately regulated by complex biochemical processes. The corruption of these regulatory processes results in aberrant TGFß signalling and leads to numerous human diseases, including cancer. Reversible ubiquitylation of pathway components is a key regulatory process that plays a critical role in ensuring a balanced response to TGFß signals. Many studies have investigated the mechanisms by which various E3 ubiquitin ligases regulate the turnover and activity of TGFß pathway components by ubiquitylation. Moreover, recent studies have shed new light into their regulation by deubiquitylating enzymes. In this report, we provide an overview of current understanding of the regulation of TGFß signalling by E3 ubiquitin ligases and deubiquitylases.

[Basic research progress of knee osteoarthritis].

The exact etiology and pathogenesis of knee osteoarthritis (KOA) are still unknown and it is hard to treat the disease fundamentally. With new therapeutic methods and techniques appearing, the present situation of treating the disease will be changed in the near future. Basic research of knee osteoarthritis will contribute to clarifying the pathogenesis and exploring the therapeutic methods. This article makes a brief review on the up-to-date basic researches of knee osteoarthritis by reviewing literature concerned in recent years.

Cells assemble invadopodia-like structures and invade into matrigel in a matrix metalloprotease dependent manner in the circular invasion assay.

The ability of tumor cells to invade is one of the hallmarks of the metastatic phenotype. To elucidate the mechanisms by which tumor cells acquire an invasive phenotype, in vitro assays have been developed that mimic the process of cancer cell invasion through basement membrane or in the stroma. We have extended the characterization of the circular invasion assay and found that it provides a simple and amenable system to study cell invasion in matrix in an environment that closely mimics 3D invasion. Furthermore, it allows detailed microscopic analysis of both live and fixed cells during the invasion process. We find that cells invade in a protease dependent manner in this assay and that they assemble focal adhesions and invadopodia that resemble structures visualized in 3D embedded cells. We propose that this is a useful assay for routine and medium throughput analysis of invasion of cancer cells in vitro and the study of cells migrating in a 3D environment.

Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling.

We previously demonstrated that the widely used immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (FK506), independent of immunophilin binding, can activate profibrogenic transforming growth factor ß (TGFß)/Smad signaling cascades in rat renal mesangial cells (MC). Here we report that both peptidyl-prolyl cis/trans isomerase (PPIase) inhibitors activate the extracellular-signaling regulated kinase (ERK) a member of the mitogen activated protein kinase (MAPK) and induce a rapid and transient increase in ERK phosphorylation. The MEK inhibitor U0126, the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), a cell-permeant superoxide dismutase (SOD) and stigmatellin, an inhibitor of mitochondrial cytochrome bc1 complex strongly attenuated the increase in ERK1/2 phosphorylation triggered by PPIase inhibitors. Moreover, neutralizing antibodies against heparin binding-epidermal growth factor (HB-EGF), and inhibition of the EGF receptor by either small interfering (si)RNA or AG1478, demonstrate that ERK activation by both PPIase inhibitors is mediated via HB-EGF-induced EGF receptor (EGFR) tyrosine kinase activation. The strong inhibitory effects achieved by GM6001 and TAPI-2 furthermore implicate the involvement of a desintegrin and metalloproteinase 17 (ADAM17). Concomitantly, the PPIase inhibitor-induced ADAM17 secretase activity was significantly reduced by SOD and stigmatellin thus suggesting that mitochondrial ROS play a primary role in PPIase inhibitor-induced and ADAM17-mediated HB-EGF shedding. Functionally, both immunosuppressants caused a strong increase in MC proliferation which was similarly impeded when cells were treated in the presence of NAC, TAPI-2 or AG1478, respectively. Our data suggest that CsA and FK506, via ROS-dependent and ADAM17-catalyzed HB-EGF shedding induce the mitogenic ERK1/2 signaling cascade in renal MC.

Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice.

When refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1, and express surface Neu3 that remove sialic acid from platelet von Willebrand factor receptor (VWFR), specifically the GPIbα subunit. The recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of inhibitors of sialidases. Desialylated VWFR is also a target for metalloproteinases (MPs), because GPIbα and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the MP inhibitor GM6001 and does not occur in Adam17(ΔZn/ΔZn) platelets expressing inactive ADAM17. Critically, desialylation in the absence of MP-mediated receptor shedding is sufficient to cause the rapid clearance of platelets from circulation. Desialylation of platelet VWFR therefore triggers platelet clearance and primes GPIbα and GPV for MP-dependent cleavage.

Perfil de expressão das metaloproteinases de matriz (MMPs) e seus inibidores (TIMP e RECK) em tumores odontogênicos benignos / Expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMP and RECK) in odontogenic tumors benign

Os tumores odontogênicos benignos compreendem um grupo de neoplasias originárias dos tecidos dentários. Pesquisas vêm buscando identificar moléculas envolvidas nos mecanismos moleculares que regulam a remodelação da matriz extracelular (MEC) e como isto influencia no comportamento localmente invasivo presente em alguns destes tumores. A Transição Epitélio-Mesenquimal (TEM conversão do fenótipo epitelial em mesenquimal) é bem caracterizada em diversos carcinomas, culminando em mestástase. MMPs são enzimas que degradam os componentes da MEC, geram moléculas bioativas, participam da TEM e o controle da remodelação da MEC dá-se pelo balanço entre elas, seus inibidores (TIMPs e RECK) e seu ativador (EMMPRIN). Assim, o objetivo deste trabalho foi delinear o perfil de expressão das MMPs (-2, -7, -9 e -14), seus inibidores (TIMPs -2, -3, -4 e RECK), seu ativador (EMMPRIN) e marcadores da TEM (Snail, Slug, N-caderina, Fibronectina, a-Actina de músculo liso e Vimentina) em Ameloblastomas (AB) e Tumores Odontogênicos Cístico Calcificantes (TOCC). Ainda, realizamos a comparação da expressão de cada molécula avaliada em cada compartimento celular (epitélio e estroma) e correlação entre as moléculas avaliadas no mesmo tumor. Utilizamos 19 casos de AB e 18 casos de TOCC (Serviço de Anatomia Patológica da FOUSP), localização das enzimas/proteínas por imunoistoquímica e analisadas nos compartimentos epitelial e estromal

Todas as proteínas/enzimas analisadas foram detectadas tanto nos AB quanto nos TOCC, sendo a maioria expressa em ambos os compartimentos. A N-caderina foi localizada apenas no epitélio dos AB e a Vimentina somente no estroma em ambos os tumores. Na comparação entre o epitélio x estroma dos ameloblastomas, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, EMMPRIN/CD147, Fibronectina, a-Actina de músculo liso, N-caderina, Vimentina, Snail e Slug. Na comparação entre o epitélio x estroma dos TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-9, RECK, EMMPRIN/CD147, Vimentina, N-caderina, Snail e Slug. Assim, entre o epitélio x estroma dos ameloblastomas e TOCC, verificamos que houve diferença estatisticamente significante (p<0,05) para a MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectina, Vimentina, a-Actina de músculo liso, N-caderina, Snail e Slug. Esta é a primeira vez que a EMMPRIN, RECK, TIMP-3, TIMP-4, Ncaderina, Snail e Slug são descritas em TOCC e TIMP-3, TIMP-4, Snail e Slug em ameloblastomas. Concluímos que estas proteínas/enzimas estão diferencialmente expressas tanto no epitélio quanto no estroma destes tumores e sugerimos que estes podem participar do comportamento localmente invasivo.

Odontogenic tumors comprise a group of benign neoplasms originating from dental tissues. Research looking for identify molecules involved in the molecular mechanisms that regulate extracellular matrix remodeling (ECM) and how this impacts on locally invasive behavior present in some of these tumors. Epithelial-Mesenchymal Transition (EMT - conversion of epithelial phenotype into mesenchymal phenotype) is well characterized in several carcinomas, leaving to metastasis. MMPs are enzymes that degrade ECM components, generate bioactive molecules, participating in the EMT and control ECM remodeling is given by the balance between them, their inhibitors (TIMPs and RECK) and its activator (EMMPRIN). The aim of this study was evaluate expression profile of MMPs (-2, -7, -9 and - 14), their inhibitors (TIMPs -2, -3, -4 and RECK), its activator (EMMPRIN) and EMT markers (Snail, Slug, N-cadherin, Fibronectin, -smooth muscle actin and Vimentin) in ameloblastomas (AB) and Calcifying Cystic Odontogenic Tumor (CCOT). We also compared the expression of each molecule assessed in each cellular compartment (epithelium and stroma) and correlation between molecules evaluated in the same tumor. We used 19 AB cases and 18 CCOT cases from files of Pathology Laboratory (FOUSP), localization of enzymes/proteins and analyzed by immunohistochemistry in epithelial and stromal compartments

All proteins/enzymes were detected in both AB and CCOT, mostly expressed in both compartments. N-cadherin was localized only in the epithelium of AB and Vimentin only in stromal in both tumors. Comparing "epithelium vs stroma" of AB, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, EMMPRIN/CD147, Fibronectin, -smooth muscle actin, N-cadherin, Vimentin, Snail and Slug. Comparing "epithelium vs stroma" of CCOT, we observed a statistically significant difference (p <0.05) for MMP-9, RECK, EMMPRIN/CD147, Vimentin, N-cadherin, Snail and Slug. Analizing epithelium vs stroma" between AB and CCOT, we observed a statistically significant difference (p <0.05) for MMP-2, MMP-7, MMP-9, RECK, EMMPRIN/CD147, Fibronectin, Vimentin , -smooth muscle actin, N-cadherin, Snail and Slug. This is the first time that EMMPRIN, RECK, TIMP-3, TIMP-4, N-cadherin, Snail and Slug are described in CCOT and TIMP-3, TIMP-4, Snail and Slug in AB. We conclude that these proteins/enzymes are differentially expressed in both epithelium and stroma of these tumors and suggest that they may participate locally invasive behavior.