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Fibrillins (FBNs) form mesh‐like structures of microfibrils in various elastic tissues. RECK and FBN1 are co‐expressed in many human tissues, suggesting a functional relationship. We found that dermal FBN1 fibers show atypical morphology in mice with reduced RECK expression (RECK‐Hypo mice). Dermal FBN1 fibers in mice‐lacking membrane‐type 1‐matrix metalloproteinase (MT1‐MMP) show a similar atypical morphology, despite the current notion that MT1‐MMP (a membrane‐bound protease) and RECK (a membrane‐bound protease inhibitor) have opposing functions. Our experiments using dermal fibroblasts indicated that RECK promotes pro‐MT1‐MMP activation, increases cell‐associated gelatinase/collagenase activity, and decreases diffusible gelatinase/collagenase activity, while MT1‐MMP stabilizes RECK in these cells. Experiments using purified proteins indicate that RECK and its binding partner ADAMTS10 keep the proteolytic activity of MT1‐MMP within a certain range. These findings suggest that RECK, ADAMTS10, and MT1‐MMP cooperate to support the formation of robust FBN1 fibers., Fibrillin‐1 fibers in the skin of mice with reduced RECK or membrane‐type 1‐matrix metalloproteinase (MT1‐MMP) deficiency show atypical morphology. Our experiments in vitro indicated that RECK, ADAMTS10, and MT1‐MMP cooperate to support the formation of robust fibrillin‐1 fibers.

A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer's disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)-anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.

© The Author(s) 2020., Matrix metalloproteinases (MMPs) occur in 23 human paralogues with key functions in physiology, and their activity is controlled by protein inhibitors. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is essential for embryogenesis and tumour suppression, has been reported to inhibit MMPs. Here, we developed eukaryotic and bacterial expression systems for different RECK variants and analysed their inhibitory capacity against representative MMPs in vitro. We could not detect any significant inhibition. Instead, we found that partially purified RECK from the conditioned medium of transfected Expi293F cells but not that of ExpiCHO-S or Drosophila Schneider cells contained a contaminant with proteolytic activity. The contaminant was removed through treatment with a small-molecule serine peptidase inhibitor and additional chromatographic purification. A tantamount contaminant was further detected in an equivalent expression system of the N-terminal fragment of the proteoglycan testican 3, but not in those of two other proteins. These results indicate that previous reports of inhibitory activity of recombinant RECK on MMPs, which were performed with partially purified samples, were probably masked by a coeluting contaminant present in the supernatant of HEK293-derived cells. Thus, RECK is probably not a direct inhibitor of MMP catalytic activity but may still regulate MMPs through other mechanisms., This study was supported in part by grants from Spanish and Catalan public and private bodies (grant/ fellowship references BFU2015–64487R, MDM-2014–0435, BES-2015–074583, BES-2016–076877, 2017SGR3 and Fundació “La Marató de TV3” 201815).

The Reversion Inducing Cysteine Rich Protein With Kazal Motifs (RECK) is a glycosylphosphatidylinositol (GPI) anchored membrane-bound regulator of matrix metalloproteinases (MMPs). It is expressed throughout the body and plays a role in extracellular matrix (ECM) homeostasis and inflammation. In initial studies, RECK expression was found to be downregulated in various invasive cancers and associated with poor prognostic outcome. Restoring RECK, however, has been shown to reverse the metastatic phenotype. Downregulation of RECK expression is also reported in non-malignant diseases, such as periodontal disease, renal fibrosis, and myocardial fibrosis. As such, RECK induction has therapeutic potential in several chronic diseases. Mechanistically, RECK negatively regulates various matrixins involved in cell migration, proliferation, and adverse remodeling by targeting the expression and/or activation of multiple MMPs, A Disintegrin And Metalloproteinase Domain-Containing Proteins (ADAMs), and A Disintegrin And Metalloproteinase With Thrombospondin Motifs (ADAMTS). Outside of its role in remodeling, RECK has also been reported to exert anti-inflammatory effects. In cardiac diseases, for example, it has been shown to counteract several downstream effectors of Angiotensin II (Ang-II) that play a role in adverse cardiac and vascular remodeling, such as Interleukin-6 (IL-6)/IL-6 receptor (IL-6R)/glycoprotein 130 (IL-6 signal transducer) signaling and Epidermal Growth Factor Receptor (EGFR) transactivation. This review article focuses on the current understanding of the multifunctional effects of RECK and how its downregulation may contribute to adverse cardiovascular remodeling.

Periodontitis is characterized by pathological destruction of extracellular matrix (ECM) of periodontal tissues. Matrix metalloproteinases (MMPs) promote the occurrence and development of periodontitis by degrading almost all proteins of ECM. RECK (reversion-inducing-cysteine-rich protein with kazal motifs), a novel membrane-anchored inhibitor of MMPs, could regulate the expression of MMP-2 and MMP-9 at post-transcriptional level. The study was to investigate the expression of RECK in healthy and diseased human gingival tissues and to correlate it with the production of MMP-2 and MMP-9.Gingival biopsies were collected from chronic periodontitis patients and periodontally healthy control individuals. The protein and mRNA of RECK, MMP-2 and MMP-9 was determined by immunohistochemistry and semi-quantitative polymerase chain reaction analysis.The expression of RECK protein was mainly confined to the gingival epithelium in inflamed and non-inflamed gingival tissues. Expression of RECK was significantly lower in tissues from chronic periodontitis patients, while the positive expression levels of MMP-2 and MMP-9 in periodontitis specimens were significantly higher. RECK protein expression was negatively correlated to the expressions of MMP-2 and MMP-9 in periodontitis. Moreover, RECK mRNA was significanly lower in diseased gingiva than in healthy samples(P0.05), while MMP-2 and MMP-9 mRNAs were observed overexpressed in periodontal lesions, with no significant correlation between RECK and MMP-2/MMP-9 mRNA shown in periodontally diseased group.The expression of RECK in human healthy and diseased gingiva may contribute to periodontal physiological and pathological processes; low RECK expression may be associated with the enhanced MMP-2 and MMP-9 production in inflamed gingiva.

Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood-brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-Å resolution and find that it folds into a compact four-helix bundle with three disulfide bonds. The CC4 structure, together with homology modeling of CC1, reveals the surface locations of critical residues that were shown in previous mutagenesis studies to mediate GPR124 binding and WNT7A/WNT7B recognition and signaling. Surprisingly, sequence and structural homology searches reveal no other cell-surface or secreted domains in vertebrates that resemble the CC domain, a pattern that is in striking contrast to other ancient and similarly sized domains, such as Epidermal Growth Factor, Fibronectin Type 3, Immunoglobulin, and Thrombospondin type 1 domains, which are collectively present in hundreds of proteins.

Cell migration is a highly conserved process involving cytoskeletal reorganization and restructuring of the surrounding extracellular matrix. Although there are many studies describing mechanisms underlying cell motility, little has been reported about the contribution of alternative isoform use toward cell migration. Here, we investigated whether alternative isoform use can affect cell migration focusing on reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an established inhibitor of cell migration. We found that a shorter isoform of RECK is more highly expressed in proliferating fibroblasts, in TGF-β–treated fibroblasts, and in tumors compared with differentiated tissue. Knockdown of this short RECK isoform reduces fibroblast migration through Matrigel. Thus, this short isoform of RECK generated by a combination of alternative splicing and alternative polyadenylation plays an opposing role to the canonical RECK isoform, as knockdown of canonical RECK results in faster cell migration through Matrigel. We show that the short RECK protein competes with matrix metalloprotease 9 (MMP9) for binding to the Kazal motifs of canonical RECK, thus liberating MMP9 from an inactivating interaction with canonical RECK. Our studies provide a new paradigm and a detailed mechanism for how alternative isoform use can regulate cell migration by producing two proteins with opposing effects from the same genetic locus.

Periodontal diseases are characterized by pathological destruction of extracellular matrix (ECM) of periodontal tissues. Matrix metalloproteinases (MMPs) are a significant part of the degradation of ECM. However, the regulation of MMPs expression level in periodontal diseases is as yet undetermined. RECK (reversion-inducing cysteine-rich protein with Kazal motifs), a novel membrane-anchored inhibitor of MMPs, could regulate the expressions of MMP-2, 9 and MT1-MMP as a cell surface-signaling molecule. Thus, we propose that RECK may play an important role in regulating MMPs in the ECM degradation of periodontal diseases. The RECK/MMPs signaling pathway could provide a new approach for prevention and treatment of RECK in periodontal diseases by blocking MMPs.

For the last three decades, metalloenzymes such as histone deacetylases (HDACs) and matrix metalloproteinases (MMPs) have been identified in promoting solid as well as hematological carcinogenesis. Histone deacetylase 8 (HDAC-8), a class I HDAC enzyme, may serve as 'epigenetic player' that affects in the regulation of transcription factors and alters the structure of chromosome associated with tumorigenesis. It is established that the influence of MMP-2 in invasion, metastasis and angiogenenic events of hematological malignancies may be suppressed by HDAC inhibitors through reversion-inducing-cysteine-rich protein with kazal motifs (RECK) protein. Therefore, the isoform-specific HDAC-8 and MMP-2 inhibitors may provide synergistic medicinal benefit in leukemia. However, a paucity of articles is available on dual acting HDAC-8/MMP-2 inhibitors. In this circumstance, a lot of works are still necessary to identify novel dual HDAC-8/MMP-2 inhibitors and this review will surely provide an initial idea regarding the utility of designing such type of dual inhibitors. Here, the importance of MMP-2 and HDAC-8 inhibition in hematological malignancies are focussed for the first time as per our knowledge along with the structure-activity relationships (SARs) of a handful of molecules, some of which were synthesised in-house, have been highlighted that will inspire more interactions between the medicinal chemistry and biology community to harness their expertise in design and discovery of the better acting dual inhibitors in future.

The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.

Objective: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) may negatively regulate matrix metalloproteinase 9 (MMP9) activity and suppress tumor invasion and metastasis. The aim of this study was to investigate whether RECK and MMP were involved in regulating middle ear carcinoma invasion and metastasis. Methods: RECK and MMP9 were measured in 30 middle ear squamous cell carcinoma tissues and 20 adjacent normal external ear canal skin tissues using immunohistochemical analysis. Results: The positive rate of RECK expression in the middle ear squamous cell carcinoma was much lower than that in the normal external ear canal skin. In contrast, the positive rate of MMP9 expression was higher in middle ear squamous cell carcinoma tissue than that in normal external ear canal skin tissue. The expressions of RECK and MMP9 were correlated with the histological grade and tumor stage, but not with patient age or gender. Conclusions: RECK and MMP9 are involved in middle ear squamous cell carcinoma and may serve as markers to evaluate progression and metastasis.

We studied the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) on peripheral blood mononuclear cells (PBMCs), the serum concentration of matrix metalloproteinase 9 (MMP-9) and the MMP-9 secretion ability of PBMCs in patients with systemic lupus erythematosus (SLE), and clinical features were assessed. Compared with PBMCs from healthy donors, PBMCs from SLE patients expressed less RECK protein and mRNA but secreted more MMP-9. The serum concentration of MMP-9 was, however, lower in SLE patients than in healthy donors. The level of RECK protein was inversely associated with the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI) and MMP-9 secretion in SLE, but no relationship was found between serum MMP-9 concentration and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). In conclusion, the level of RECK protein expressed in PBMCs could be used to predict organ or system damage in SLE and this might help in developing new therapies for SLE targeted at MMP-9.

We examined expression patterns of matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in colorectal cancer tissues to assess their prognostic significance.mRNA expressions of 17 MMPs, 4 TIMPs, and RECK were measured in 112 colorectal cancerous tissues, 20 normal mucosa tissues, and 11 metastatic liver lesions by real-time reverse-transcriptional-polymerase chain reaction. The protein level expressions were confirmed with immunohistochemistry.Cancers and normal mucosa displayed highly significant differences (P0.01) in expression of nine genes (MMP-1, -3, -7, -9, -10, -11, -12, -14, and RECK). Primary cancers and metastatic lesions showed highly significant differences (P0.01) in MMP-1, -10, -11, and TIMP-1. MMP-12 expression was higher in the primary tumors that were associated without hepatic metastasis than those with metastasis (P0.01). High expression of MMP-15 was related to longer disease-free survival (generalized Wilcoxon test, P0.0062; Cox hazard model, P0.028, hazard ratio, 0.099).MMP, TIMP, RECK expression patterns may provide an insight into extracellular matrix degrading (which is characteristic of colorectal cancers) and its role in metastasis.

RECK is a membrane-anchored glycoprotein which may negatively regulate matrix metalloproteinase (MMP) activity to suppress tumor invasion and metastasis. In this study, recombinant proteins corresponding to the residues 285-368 (named as CKM which contained cysteine knot motif), 605-799 (named as K123 which contained three Kazal motifs), 676-799 (named as K23 which contained the last two Kazal motifs) and full-length RECK were produced and their anti-cancer effects were tested. Full-length RECK and K23 but not K123 and CKM inhibited MMP9 secretion and activity. In addition, RECK and K23 inhibited invasion but not migration of metastatic lung cancer cells in vitro. Protein binding and kinetic study indicated that K23 physically interacted with MMP-9 and inhibited its activity by a non-competitive manner. Moreover, K23 reduced metastatic tumor growth in lungs of nude mice. Taken together, our results suggest that the K23 motifs of RECK protein can inhibit MMP-9 secretion and activity and attenuate metastasis of lung cancer cells.

The present study examined the role of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) promoter hypermethylation as a causative factor in metastasis of osteosarcoma. Using human pathological samples, it is demonstrated that RECK, a cysteine protease that reversibly regulates expression of matrix metalloproteases like matrix metallopeptidase 9 (MMP9), is transcriptionally inhibited in osteosarcoma, especially metastatic variants. This result comes from its promoter hypermethylation, as evaluated in the present study by methylation-specific PCR reaction. The expression of RECK was also significantly diminished in the metastatic variants of osteosarcoma. This downregulation of RECK in advanced grades of osteosarcoma and metastatic grades was also associated with the increased expression of invadosome-specific markers like MMP9, phospho-FAK, and integrins, suggesting the complex contributions of RECK in the prevention of metastasis and its downregulation as a causative factor in osteosarcoma metastasis.

Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase inhibitor, and experimental studies have shown that RECK can suppress tumor progression through angiogenesis inhibition. We have already revealed that enhanced RECK expression is significantly correlated with a favorable prognosis in non-small-cell lung cancer (NSCLC). In this study, further analyses focused on pN2 disease were conducted to assess the clinical significance of RECK expression.A total of 118 patients with completely resected pathologic stage IIIA N2 NSCLC were retrospectively examined. RECK expression in the primary tumor, along with involved N2 nodes, was examined immunohistochemically.RECK expression in the primary tumor was strong in 53 patients (44.9%) and was weak in the other 65 patients. The 5-year survival rate of patients with RECK-strong tumor (42.9%) was significantly higher than that of patients with RECK-weak tumor (23.1%; P = .017). Reduced RECK expression significantly correlated with a poor prognosis for patients with a single N2 node involved (P = .019), but not for patients with multiple N2 nodes involved (P = .440). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031). RECK expression in involved N2 nodes was significantly higher than in primary tumors (P.001).RECK status was a novel prognostic factor in pathologic stage IIIA N2 NSCLC.

The invasive phenotype of many tumors is associated with an imbalance between the matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the membrane-anchored reversion-inducing cysteine-rich protein with Kazal motifs (RECK). RECK inhibits MMP-2, MMP-9, and MT1-MMP, and has been linked to patient survival and better prognosis in several types of tumors. However, despite the wide implication of these MMPs in melanoma establishment and progression, the role of RECK in this type of tumor is still unknown. Here, we analyzed the expression of RECK, TIMP1, TIMP2, TIMP3, MT1MMP, MMP2, and MMP9 in two publicly available melanoma microarray datasets and in a panel of human melanoma cell lines. We found that RECK is downregulated in malignant melanoma, accompanied by upregulation of MT1MMP and TIMP2. In both datasets, we observed that the group of samples displaying higher RECK levels show lower median expression levels of MT1MMP and TIMP2 and higher levels of TIMP3. When tested in a sample-wise manner, these correlations were statistically significant. Inverse correlations between RECK, MT1MMP, and TIMP2 were verified in a panel of human melanoma cell lines and in a further reduced model that includes a pair of matched primary tumor-derived and metastasis-derived cell lines. Taken together, our data indicate a consistent correlation between RECK, MT1MMP, and TIMP2 across different models of clinical samples and cell lines and suggest evidence of the potential use of this subset of genes as a gene signature for diagnosing melanoma.

microRNAs play critical roles in the progression and metastasis of nonsmall cell lung cancer (NSCLC). miR-92b acts as an oncogene in some malignancies; however, its role in NSCLC remains poorly understood. Here, we found that miR-92b was significantly increased in human NSCLC tissues and cell lines. Inhibition of miR-92b remarkably suppressed cell proliferation, migration, and invasion of NSCLC cells. Reversion-inducing-cysteine-rich protein with kazal motifs (RECK) was identified to be a target of miR-92b. Expression of miR-92b was negatively correlated with RECK in NSCLC tissues. Collectively, miR-92b might promote NSCLC cell growth and motility partially by inhibiting RECK.

In this study, we found that the expression of miR-15a was positively correlated with neuroblastoma (NB) clinical pathological stage and was negatively correlated with reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression. Using the enhanced green fluorescent protein (EGFP) reporter construct carrying the 3'-UTR of RECK, we identified RECK as a direct target of miR-15a. Suppression of miR-15a significantly decreased the migration ability of GI-LA-N and SK-N-SH cell lines, whereas overexpression of miR-15a increased the migration ability; these effects could be partly reversed by RECK inhibition or ectopic expression. Moreover, inhibition of miR-15a significantly increased secreted matrix metalloproteinase-9 expression in culture medium through regulating the expression of RECK. These findings provide new insights into the characteristics of the miR-15a-RECK-matrix metalloproteinase-9 axis in NB progression, especially in NB migration and invasion.

RECK (reversion-inducing cysteine-rich protein with Kazal motifs) is a membrane-anchored glycoprotein which regulates MMP2 and MMP9 activity and has been proposed to play a role in embryo implantation while misexpression of RECK has been associated with a variety of carcinomas. Unfortunately, understanding on the steroidal regulation of uterine RECK is lacking. To address this gap in our knowledge, we examined steroidal regulation and cellular expression of Reck mRNA and protein within the mouse uterus in vivo. Uterine Reck mRNA and protein were decreased by estrogen, while progesterone alone had no effect. The estrogen-induced down regulation could be partially blocked by progesterone. RECK was localized primarily to luminal and glandular epithelial cells and the level of expression was regulated in a similar fashion as in whole tissue by the steroids. Knock-down of endogenous RECK in human endometrial epithelial and stromal cells resulted in a significant increase in active MMP9 expression but not that of pro-MMP9 or MMP2. These studies demonstrate that RECK expression in the mouse uterus is steroidally regulated and that within endometrial epithelial and stromal cells, RECK regulates MMP9, but not MMP2 activity.

Reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored glycoprotein that negatively regulates the activities of matrix metalloproteinases (MMPs) and inhibits tumor invasion, metastasis, and angiogenesis. RECK is essential for normal development and is a key mediator of tissue remodeling and stabilization of tissue architechture. Downregulation of RECK documented in a wide range of malignant neoplasms correlates with poor prognosis, and tumor metastasis. The RECK gene is a common negative target for oncogenic signals that act on the Sp1-binding site of the RECK promoter. Both natural and synthetic agents have been identified as upregulators of RECK. Several strategies have been proposed to enhance RECK expression including forced expression of RECK, use of mimetics, recombinant peptides, microRNA antagonists, and gene therapy. Upregulation of RECK could be a valuable therapeutic option to improve prognosis and block tumor progression. This review addresses the potential value of RECK as a prognostic marker and as a molecular target for cancer therapy.

Patient prognosis in colorectal cancer is determined as in most solid cancers by the extent of local invasion and the presence of lymph node and distant metastases. The invasive potential of a tumor depends on the ability to degrade extracellular matrix proteins, for example, by matrix metalloproteinases. An important inhibitor of matrix metalloproteinases is reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein. This study investigated the prognostic relevance of RECK expression in colorectal cancer in a cohort of 283 patients. Analysis of immunohistochemical tissue microarray data showed that RECK protein levels did not seem to correlate with clinicopathologic parameters (Spearman rank correlation coefficients between -0.14 and -0.18) and that decreased RECK expression was an independent prognostic factor of poor survival, with a mean survival of 70 months in RECK-negative (146 cases) versus 97 months in RECK-positive patients (137 cases) (log-rank test, P = .002).

Prognosis of chordomas is difficult to predict based solely on histological findings. The purpose of this study was to assess expressions of reversion-inducing cysteine-rich protein with kazal motifs (RECK) and matrix metalloproteinase (MMP)-2, MMP-9 in skull base chordomas and to find out their correlations to outcome. Immunohistochemical study was performed in 19 samples (initial, n = 11; recurrent, n = 8) from 11 patients. The correlations among expression of RECK, MMP-2, MMP-9, and their prognostic values were analyzed. Significant correlation between RECK and MMP-9 was found, but there was no correlation found between MMP-2 and MMP-9. Higher MMP-9 expression significantly influenced outcome. Furthermore, MMP-9/RECK ratio showed significant correlation to outcome, showing their inverse relationship in the disease progress of skull base chordoma. RECK and MMP-9 can be valuable markers to predict prognosis in skull base chordomas., Article, NEUROSURGICAL REVIEW. 33(2):167-173 (2010)

Cancer recurrence after surgical treatment is a major concern for patients and doctors. Understanding what makes tumors prone to recurrence would be an important step toward its prevention. Accumulating evidence indicates that the level of membrane-associated protease regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expressed in tumor tissue is a good prognostic indicator in several common cancers. Certain members of the matrix metalloproteinase family are often upregulated in advanced cancers and are known to play important roles in tumor angiogenesis, invasion and metastasis. RECK negatively regulates several matrix metalloproteinases. Therefore, RECK itself may well be considered a promising tool or target molecule to be activated in cancer therapy. Here we review the recent advances in RECK research and discuss some of the important issues to be addressed in future studies.

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is anchored to the cell surface via glycosylphosphatidylinositol. This molecule antagonizes the function of membrane type 1 matrix metalloproteinase (MT1-MMP) to promote proMMP-2 maturation. Here, we attempt to clarify the mechanism underlying RECK functions. First, we found that RECK forms a complex with MT1-MMP and inhibits its proteolytic activity. Notably, RECK increases the amount of MT1-MMP that associates with detergent-resistant membranes during sucrose gradient ultracentrifugation. Furthermore, perturbation of membrane cholesterol significantly affected the function of RECK in suppressing MT1-MMP function. These findings indicate that RECK possibly regulates MT1-MMP function by modulating its behavior on the cell surface as well as by enzymatic action; this prompted us to find another molecule whose behavior in detergent-resistant membranes is influenced by RECK. Subsequently, we found that RECK interacts with CD13/aminopeptidase N. Further, we found that RECK inhibits the proteolytic activity of CD13 in a cholesterol perturbation-sensitive manner. Finally, we examined whether RECK influences the behavior of MT1-MMP and CD13 during their internalization from the cell surface. In the absence of RECK, MT1-MMP and CD13 were internalized along with the markers of clathrin- or caveolae-dependent endocytosis. However, interestingly, in the presence of RECK these molecules were internalized preferentially with an endocytic marker that is neither clathrinnor caveolae-dependent, indicating that RECK modulates endocytic pathways of MT1-MMP and CD13. This modulation was correlated with the accelerated internalization and decay of MT1-MMP and CD13. This study unveils the novel function and target molecules of RECK.

Contains fulltext : 51160.pdf (Publisher’s version ) (Closed access) mRNA, and latent and active levels MMP-2 and -9 were higher in tumor tissue compared to normal tissue from 63 patients with colorectal cancer, whereas RECK and EMMPRIN levels were lower. Correlations between mRNA, latent, and active MMP were particular high for MMP-2 in tumor tissue (R(s)=0.6-0.8, P

In this study the expression levels of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) in gastric cancer cell lines and tissues have been analysed in order to assess their value as a prognostic indicator. The expressions of RECK, activated matrix metalloproteinase (MMP)-7, and vascular endothelial growth factor (VEGF) in gastric cancer tissues and cell lines were evaluated by Western blot analysis; and MMP-2 and MMP-9 were evaluated by gelatin zymography. RECK expression in the context of gastric cancer was also compared with various clinicopathologic parameters and compared to the expression of activated MMP-7, MMP-2, and MMP-9. Fifty-two percent of the 102 gastric cancer tissues and 81.8% of the 11 gastric cancer cell lines exhibited reduced RECK expression. We also detected a significant inverse correlation between RECK expression and macroscopic tumour growth (P = 0.018), lymphatic invasion (P = 0.018), lymph node metastasis (P = 0.000), stage (P = 0.000), and MMP-9 (P = 0.039). No correlation between RECK expression and MMP-7 and MMP-2, VEGF were detected. Our data strongly supports the hypothesis that RECK is a suppressor of malignancy, and constitutes a good prognostic indicator in gastric cancer.

Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the matrix metalloproteinase (MMP) sub-family, exhibiting varying efficacy against different members, as well as different tissue expression patterns and modes of regulation. Other proteins have modest inhibitory activity against some of the MMPs, including domains of netrins,the procollagen C-terminal proteinase enhancer (PCPE), the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and tissue factor pathway inhibitor (TFPI-2), but their physiological significance is not at all clear.α2-Macroglobulin, thrombospondin-1 and thrombospondin-2 can bind to some MMPs and act as agents for their removal from the extracellular environment. In contrast, few effective inhibitors of other members of the metzincin family, the astacins or the distintegrin metalloproteinases, ADAMs have been identified.Many of these MMP inhibitors, including the TIMPs, possess other biological activities which may not be related to their inhibitory capacities. These need to be thoroughly characterized in order to allow informed development of MMP inhibitors as potential therapeutic agents. Over activity of MMPs has been implicated in many diseases, including those of the cardiovascular system,arthritis and cancer. The development of synthetic small molecule inhibitors has been actively pursued for some time, but the concept of the use of the natural inhibitors, such as the TIMPs, in gene based therapies is being assessed in animal models and should provide useful insights into the cell biology of degradative diseases.

BACKGROUND: The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03-3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. CONCLUSIONS: RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan.