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PubMed2005

Cyclin-dependent kinase inhibitors and JNK act as molecular switches, regulating the choice between growth arrest and apoptosis induced by galectin-8.

Galectin-8, a mammalian beta-galactoside binding lectin, functions as an extracellular matrix protein that forms high affinity interactions with integrins. Here we demonstrated that soluble galectin-8 inhibits cell cycle progression and induces growth arrest. These effects cannot be attributed to interference with cell adhesion but can be attributed to a 4-5-fold increase in the cellular content of the cyclin-dependent kinase inhibitor p21, which was already evident following a 4-h incubation of H1299 cells with galectin-8. The increase in p21 levels was preceded by a 3-5-fold increase in JNK and protein kinase B (PKB) activities. Accordingly, SP600125, the inhibitor of JNK, and wortmannin, the inhibitor of phosphatidylinositol 3-kinase, which is the upstream activator of PKB, inhibited the increase in the cellular content of p21. Furthermore, overexpression of a dominant inhibitory form of SEK1, the upstream kinase regulator of JNK, inhibited both JNK activation and p21 accumulation. When p21 expression was inhibited by cycloheximide, galectin-8 directed the cells toward apoptosis, which involves induction of poly(ADP-ribose) polymerase cleavage. Indeed, galectin-8-induced apoptosis was 2-fold higher in HTC (p21-null) cells when compared with parental HTC cells. Because overexpression of galectin-8 attenuates the rate of DNA synthesis, stable colonies that overexpress and secrete galectin-8 can be generated only in cells overexpressing a growth factor receptor, such as the insulin receptor. These results implicate galectin-8 as a modulator of cellular growth through up-regulation of p21. This process involves activation of JNK, which enhances the synthesis of p21, combined with the activation of PKB, which inhibits p21 degradation. These effects of the lectin depended upon protein-sugar interactions and were induced when galectin-8 was present as a soluble ligand or when it was overexpressed in cells.

Androstadienes↗

PubMed2000

Expression pattern of galectin-3 in neural tumor cell lines.

Galectin-3 is a member of the galectin family of beta-galactoside-specific animal lectins. Here we show that galectin-3 is constitutively expressed in 15 out of 16 glioma cell lines tested, but not by normal or reactive astrocytes, oligodendrocytes, glial O-2A progenitor cells and the oligodendrocyte precursor cell line Oli-neu. Galectin-3 is also expressed by one oligodendroglioma cell line, but not by primitive neuroectodermal tumor and 4 neuroblastoma cell lines tested so far. In all galectin-3 expressing cell lines, the lectin is predominantly, if not exclusively, localized intracellularly and carries an active carbohydrate recognition domain (shown for C6 rat glioma cells). Moreover, in contrast to primary astrocytes, glioma cells do not or only weakly adhere to substratum-bound galectin-3, probably reflecting an unusual glycosylation pattern. Our findings indicate that the expression of galectin-3 selectively correlates with glial cell transformation in the central nervous system and could thus serve as a marker for glial tumor cell lines and glial tumors.

Animals↗

PubMed1996

Galectin-3 promotes adhesion of human neutrophils to laminin.

Galectin-3 is a member of a growing family of animal lectins composed of three domains, with the amino-terminal half consisting of a short segment followed by tandem repeats, and the carboxyl-terminal half representing the carbohydrate-recognition domain. Previously, we have shown that galectin-3 binds to the surface of human neutrophils and is capable of activating these cells. We have now studied the effect of exogenous galectin-3 on adhesion of human neutrophils to laminin-coated microtiter plates and found that this lectin promotes the adhesion in a dose-dependent manner. The effect was dependent on the lectin's carbohydrate-binding function, as well as its amino-terminal region. The galectin-3-induced adhesion was reduced significantly in the presence of EDTA, even though Ca2+ and Mg2+ are not required for the lectin binding, and the adhesion was significantly less at 4 degrees C, as compared with 37 degrees C. Galectin-3 also induced neutrophil adhesion to fibronectin, which is not recognized by the lectin, but much higher concentrations of the lectin were required, and the effect is completely dependent on Ca2+ and Mg2+. We conclude that galectin-3 induces neutrophil adhesion to laminin through a combination of two distinct mechanisms: 1) the lectin bridges neutrophils to laminin, in a carbohydrate-dependent and Ca2+-, Mg2+-independent manner, and 2) the lectin induces activation of neutrophils, in the presence of the divalent cations, resulting in the positive regulation of other cell adhesion molecules and enhanced adhesion to laminin. The results suggest that galectin-3 may play a role in the traversing of neutrophils through the basement membrane at inflammation sites.

Amino Acid Sequence↗

PubMed2001

[Rheumatoid arthritis: new developments in the pathogenesis with special reference to synovial fibroblasts].

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is mainly characterized by synovial hyperplasia, pathological immune phenomena and progressive destruction of the affected joints. Various cell types are involved in the pathogenesis of RA including T cells, antigen presenting cells, and endothelial cells. Recent experimental evidence suggests that the CD40/CD154 system might play an important role in the development of RA. Our experimental approach focuses on RA synovial fibroblasts (RA-SF) that are able to destroy articular cartilage independent of inflammation. To elucidate the specific role of those cells in RA pathophysiology the following questions are currently addressed: 1. Which mechanisms do activate the RA-SF? 2. How do the activated RA-SF attach to the cartilage? 3. How do RA-SF destroy cartilage and bone? Which mechanisms do activate the RA-SF? The process of activation is poorly understood. It is unclear, how far the synovial hyperplasia of RA resembles tumor diseases. Along this line some contradictory results exist concerning the role of the tumor suppressor protein p53. Some investigations could show the expression of p53 in the synovial lining including p53 mutations in RA synovium and in RASF, while other research groups could not confirm these data. Our group has demonstrated that the tumor suppressor PTEN was less expressed in the synovial lining of RA than in normal synovium, but no PTEN mutations could be found in the RA-SF. In addition, the in vivo and in vitro expression of the anti-apoptotic molecule sentrin suggests a functional resistance of RA-SF to undergo apoptosis. Although it is still unclear, whether certain viruses or viral elements are involved in the pathogenesis of RA (cause, consequence or coincidence?), certain viruses could play a role in the pathogenesis of RA. The endogenous retroviral element L1 was found to be expressed in the synovial lining, at sites of invasion as well as in RA-SF grown in vitro. Moreover, the data indicate that after the initial activation of L1 downstream molecules such as the SAP kinase 4, the met-protoonocogene and the galectin-3 binding protein are upregulated. How do the activated RA-SF attach to the cartilage? It has been suggested that integrins mediate the attachment of RA-SF to fibronectin rich sites of cartilage. Intriguingly, other adhesion molecules such as the vascular cellular adhesion molecule-1 (VCAM) and CS-1, a splice variant of fibronectin, are synthesized by RA-SF. By binding to these adhesion molecules, lymphocytes that express the integrin VLA-4 could be stimulated and thereby maintain the inflammatory process. Osteopontin is an extracellular matrix protein, which is associated with matrix adhesion and metastasis in tumors. In RA synovium, osteopontin was detectable in the synovial lining and at sites of invasion. How do RA-SF destroy cartilage and bone? The destruction of cartilage and bone in RA is mediated by matrix metalloproteinases (MMPs) and cathepsins. MMPs exist as secreted and as membrane bound forms. In vitro models are being developed to simulate the invasive process of RA-SF. In an in vitro model developed in our laboratory, the treatment of RA-SF with anti-CD44 or anti-interleukin-1 (IL-1) minimized matrix degradation of RA-SF. On the other hand, co-culture of RA-SF and U937 cells as well as application of interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) increased the invasiveness of RA-SF. Gene transfer of bovine pancreas trypsin inhibitor (BPMI) or interleukin-10 (IL-10) reduced the invasion of RA-SF, while transduction of interleukin-1 receptor antagonist (IL-1Ra) was chondroprotective. Double gene transfer of IL-10 and IL-1Ra resulted in both inhibition of invasion and chondroprotection.

Arthritis, Rheumatoid↗

PubMed2006

Human monocytes recognize porcine endothelium via the interaction of galectin 3 and alpha-GAL.

Monocytes are one of the key inflammatory cells recruited to xenografts and play an important role in delayed xenograft rejection. Previous studies have demonstrated the ability of monocytes to bind to the major xenoantigen Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R; however, the receptor that mediates this interaction has yet to be identified. We provide evidence that it is Galectin-3, a approximately 30-kDa lectin that recognizes beta-galactosides (Gal-beta(1-3/4)GlcNAc) and plays diverse roles in many physiological and pathological events. Human monocyte binding is strikingly increased on porcine aortic endothelial cells (PAEC), which express high levels of Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R, compared with human aortic endothelial cells. Human monocytes obtained from healthy donors bind to Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R at variable intensities. This variation of binding intensity was consistent and reproducible in individual donors. Galectin-3 is mainly expressed in human monocytes, not lymphocytes. Purified Galectin-3 is able to bind directly to Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R. Galectin-3 can also be affinity isolated from monocytes (and not lymphocytes) using an Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R-biotin/streptavidin-bead pull-down system. Soluble Galectin-3 binds preferentially to PAEC vs human aortic endothelial cells, and this binding can be inhibited by lactose, indicating dependence on the carbohydrate recognition domain of Galectin-3. Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R is at least partly responsible for this phenomenon, as binding decreased after digestion of PAEC with alpha-galactosidase. Furthermore, monocytes pretreated with a blocking anti-Galectin-3 Ab show decreased adhesion to PAEC when compared with isotype control in a parallel plate flow chamber perfusion assay. Thus, we conclude that Galectin-3 expressed in human monocytes is a receptor for the major xenoantigen (Gal-alpha(1,3)Gal-beta(1,4)GlcNAc-R), expressed on porcine endothelial cells.

Animals↗

PubMed1998

Galectin-3 expression in human atherosclerotic lesions.

The expression of galectin-3, a beta-galactoside-binding lectin, was studied in atherosclerotic lesions from specimens obtained from carotid endarterectomies, lower limb amputations, and thoracic aortas from autopsies of young adult trauma victims. Immunohistochemical staining with the monoclonal antibody M3/38 demonstrated the presence of galectin-3 in advanced atherosclerotic lesions from each of 13 cases of carotid endarterectomy and 16 lower limb amputations and in the thoracic aorta of 4 of 20 cases of trauma victim adults. Immunostaining did not detect galectin-3 in umbilical cord and normal thoracic aorta arteries and limb veins. Dual immunostaining with monoclonal antibodies M3/38 for galectin-3 and clone 1A4 for smooth muscle alpha-actin or HAM56 for human macrophage antigen showed that galectin-3 was localized predominantly in foam cells and macrophages and rarely (<5%) in the smooth muscle cells of atherosclerotic lesions. The incidence of galectin-3-positive cells was higher in the carotid artery atherosclerotic lesions, which are richer in foam cells, than in the lower limb atherosclerotic lesions, which are more fibrotic. Reverse transcription polymerase chain reaction showed a significantly higher ratio of galectin-3/beta-actin transcripts in 20 atherosclerotic arteries compared with that of 5 umbilical cord arteries. Western blot analysis confirmed a higher level of galectin-3 in atherosclerotic carotid and lower limb arteries compared with that of umbilical cord arteries. The increased expression of galectin-3 in atherosclerotic lesions suggests the involvement of this multifunctional protein in atherogenesis.

Actins↗

PubMed2002

Oligosaccharide specificity of galectins: a search by frontal affinity chromatography.

Galectins are widely distributed sugar-binding proteins whose basic specificity for beta-galactosides is conserved by evolutionarily preserved carbohydrate-recognition domains (CRDs). Although they have long been believed to be involved in diverse biological phenomena critical for multicellular organisms, in only few a cases has it been proved that their in vivo functions are actually based on specific recognition of the complex carbohydrates expressed on cell surfaces. To obtain clues to understand the physiological roles of diverse members of the galectin family, detailed analysis of their sugar-binding specificity is necessary from a comparative viewpoint. For this purpose, we recently reinforced a conventional system for frontal affinity chromatography (FAC) [J. Chromatogr., B, Biomed. Sci. Appl. 771 (2002) 67-87]. By using this system, we quantitatively analyzed the interactions at 20 degrees C between 13 galectins including 16 CRDs originating from mammals, chick, nematode, sponge, and mushroom, with 41 pyridylaminated (PA) oligosaccharides. As a result, it was confirmed that galectins require three OH groups of N-acetyllactosamine, as had previously been denoted, i.e., 4-OH and 6-OH of Gal, and 3-OH of GlcNAc. As a matter of fact, no galectin could bind to glycolipid-type glycans (e.g., GM2, GA2, Gb3), complex-type N-glycans, of which both 6-OH groups are sialylated, nor Le-related antigens (e.g., Le(x), Le(a)). On the other hand, considerable diversity was observed for individual galectins in binding specificity in terms of (1) branching of N-glycans, (2) repeating of N-acetyllactosamine units, or (3) substitutions at 2-OH or 3-OH groups of nonreducing terminal Gal. Although most galectins showed moderately enhanced affinity for branched N-glycans or repeated N-acetyllactosamines, some of them had extremely enhanced affinity for either of these multivalent glycans. Some galectins also showed particular preference for alpha1-2Fuc-, alpha1-3Gal-, alpha1-3GalNAc-, or alpha2-3NeuAc-modified glycans. To summarize, galectins have evolved their sugar-binding specificity by enhancing affinity to either "branched", "repeated", or "substituted" glycans, while conserving their ability to recognize basic disaccharide units, Galbeta1-3/4GlcNAc. On these bases, they are considered to exert specialized functions in diverse biological phenomena, which may include formation of local cell-surface microdomains (raft) by sorting glycoconjugate members for each cell type.

Animals↗

PubMed2003

Molecular dynamics simulations of galectin-1-oligosaccharide complexes reveal the molecular basis for ligand diversity.

Galectin-1 is a member of a protein family historically characterized by its ability to bind carbohydrates containing a terminal galactosyl residue. Galectin-1 is found in a variety of mammalian tissues as a homodimer of 14.5-kDa subunits. A number of developmental and regulatory processes have been attributed to the ability of galectin-1 to bind a variety of oligosaccharides containing the Gal-beta-(1,4)-GlcNAc (LacNAc(II)) sequence. To probe the origin of this permissive binding, solvated molecular dynamics (MD) simulations of several representative galectin-1-ligand complexes have been performed. Simulations of structurally defined complexes have validated the computational approach and expanded upon data obtained from X-ray crystallography and surface plasmon resonance measurements. The MD results indicate that a set of anchoring interactions between the galectin-1 carbohydrate recognition domain (CRD) and the LacNAc core are maintained for a diverse set of ligands and that substituents at the nonreducing terminus of the oligosaccharide extend into the remainder of a characteristic surface groove. The anionic nature of ligands exhibiting relatively high affinities for galectin-1 implicates electrostatic interactions in ligand selectivity, which is confirmed by a generalized Born analysis of the complexes. The results suggest that the search for a single endogenous ligand or function for this lectin may be inappropriate and instead support a more general role for galectin-1, in which the lectin is able to crosslink heterogeneous oligosaccharides displayed on a variety of cell surfaces. Such binding promiscuity provides an explanation for the variety of adhesion phenomena mediated by galectin-1.

Computer Simulation↗

PubMed2024

Value of a secretomic approach for distinguishing patients with COVID-19 viral pneumonia among patients with respiratory distress admitted to intensive care unit.

In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with Nonviral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. The objective of this study is to identify the secretomic signatures of VPP with those of NV-ICU. Plasma samples and clinical data from NV-ICU (n = 104), VPP (n = 30) or healthy donors (HD, n = 20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using nontarget mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. We describe five of the best combinations of 3 proteins (complement component C9, Ficolin-3, Galectin-3-binding protein, Fibrinogen alpha, gamma and beta chain, Proteoglycan 4, Coagulation factor IX and Cdc42 effector protein 4) that show a characteristic receptor function curve with an area under the curve of 95.0%. This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations.

Humans↗

PubMed2006

Molecular characterization and oligosaccharide-binding properties of a galectin from the argasid tick Ornithodoros moubata.

The argasid tick Ornithodoros moubata is a vector of various viral and borrelian diseases in animals and humans. We report here molecular characterization and oligosaccharide-binding properties of a novel galectin (OmGalec) from this tick. OmGalec consisted of 333 amino acids with a predicted molecular weight of 37.4 kDa. Its amino acid sequence did not contain a signal peptide or transmembrane domain. It possessed tandem-repeated carbohydrate recognition domains, in which the typical motifs important for carbohydrate affinity were conserved. OmGalec was expressed both transcriptionally and translationally at all stages of the tick life cycle and in multiple organs and was abundant in hemocytes, midguts, and reproductive organs, which are of importance in immunity, interaction with pathogens, and development, respectively, suggesting that OmGalec is a multifunctional molecule. The oligosaccharide affinity profile analyzed by applying an automated frontal affinity chromatography system revealed that rOmGalec showed a general feature of the galectin family, i.e. significant affinity for lactosamine-type disaccharides, Galbeta1-3(4)Glc(NAc), via recognition of 4-OH and 6-OH of galactose and 3 (4)-OH of Glc(NAc). Its preference for type I saccharides and alpha1-3GalNAc-containing oligosaccharides might provide clues for identifying its ligands and its potential multiple functions. Our results may contribute to the elucidation of galectin functions in the development and immunity of arthropods and/or vector and pathogen interaction and provide valuable information for the development of novel tick control strategies.

Amino Acid Sequence↗

PubMed2001

Immunohistochemical profile of galectin-8 expression in benign and malignant tumors of epithelial, mesenchymatous and adipous origins, and of the nervous system.

This study aims to investigate whether the immunohistochemical expression of galectin-8 could be used as a diagnostic marker in tumor tissues of various histogenetic origins including specimens from epithelial (n=145), mesenchymatous (n=16), adipous (n=10) and central and peripheral nervous system (n=25) tissue, and 4 mesotheliomas. Immunohistochemical reactions were carried out with a polyclonal anti-galectin-8 antibody and histological slides from tissues derived from the files of the Laboratory of Anatomopathology of University Erasmus Hospital, Brussels. Formalin-fixed paraffin-embedded tissues of 45 normal cases as well as 41 benign and 114 malignant tumors were studied. Marked decreases in immunohistochemical galectin-8 expression were observed in colon (p=0.001), pancreas (p=0.007), liver (p=0.0008), skin (p=0.002) and larynx (p=0.02) tissue when comparing malignant tissue to normal tissue and/or benign tumors. The reverse relationship was observed for breast tissue (p=0.007). No statistically significant differences (p>0.05) were detected when comparing normal tissue and/or benign to malignant tumors in lung, bladder, kidney, prostate and stomach tissue. Significant galectin-8 expression was also measured in non-epithelial tissue including tumors of the central and peripheral nervous system as well as in skeletal muscle and mesotheliomas. Immunohistochemical monitoring of galectin-8 thus reveals an organ-type-dependent regulation of expression upon malignant transformation of various tissue types of epithelial origin. This observation will prompt further studies to delineate any relationship with prognosis.

Adipose Tissue↗

PubMed2001

Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.

Several molecules were shown to bind advanced glycation end products (AGEs) in vitro, but it is not known whether they all serve as AGE receptors and which functional role they play in vivo. We investigated the role of galectin-3, a multifunctional lectin with (anti)adhesive and growth-regulating properties, as an AGE receptor and its contribution to the development of diabetic glomerular disease, using a knockout mouse model. Galectin-3 knockout mice obtained by gene ablation and the corresponding wild-type mice were rendered diabetic with streptozotocin and killed 4 months later, together with age-matched nondiabetic controls. Despite a comparable degree of metabolic derangement, galectin-3-deficient mice developed accelerated glomerulopathy vs. the wild-type animals, as evidenced by the more pronounced increase in proteinuria, extracellular matrix gene expression, and mesangial expansion. This was associated with a more marked renal/glomerular AGE accumulation, indicating it was attributable to the lack of galectin-3 AGE receptor function. The galectin-3-deficient genotype was associated with reduced expression of receptors implicated in AGE removal (macrophage scavenger receptor A and AGE-R1) and increased expression of those mediating cell activation (RAGE and AGE-R2). These results show that the galectin-3-regulated AGE receptor pathway is operating in vivo and protects toward AGE-induced tissue injury in contrast to that through RAGE.

Animals↗

PubMed2003

Evaluation of galectin-3 expression by sarcomas, pseudosarcomatous and benign lesions of the soft tissues. Preliminary results of an immunohistochemical study.

Galectin-3 is an endogenous galactose-binding protein that is expressed in several normal and neoplastic tissues and is thought to play a role in a variety of biological processes. In this study we have examined the immunohistochemical expression pattern of galectin-3 in the most representative categories of soft tissue tumors consisting of 162 patients' specimens. Lesions were classified according to histogenetic criteria into 13 major categories. Overall, there were 18 fibrous tumors (13 benign, 4 intermediate and 1 malignant), 21 fibrohistiocytic tumors (5 benign, 11 intermediate and 5 malignant), 22 lipomatous tumors (14 benign and 8 malignant), 20 smooth muscle tumors (12 benign, 5 intermediate and 3 malignant), 2 skeletal muscle tumors (2 malignant), 19 vascular tumors (9 benign and 10 malignant), 6 perivascular tumors (5 benign and 1 malignant), 7 synovial tumors (4 benign and 3 malignant), 3 benign mesothelial tumors, 27 neural tumors (25 benign and 2 malignant), 7 cartilaginous and osseous tumors (4 benign and 3 malignant), 8 miscellaneous tumors and 2 high grade unclassified sarcomas. Galectin-3 was constantly expressed by almost all the major categories of benign, pseudosarcomatous and malignant soft tissue tumors. At this time no data are available in the literature about the expression of galectin-3 distribution in a wide range of soft tissue tumors. In the present work we discuss the significance and the possible usefulness of such findings.

Cell Nucleus↗

PubMed2006

Galectin-3 immunoprofile in adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma of salivary glands.

Adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA) are malignant neoplasms of salivary glands, which are similar in histologic patterns but very different in clinical behavior, treatment and prognosis. Galectin-3 is a multifunctional protein of a growing family of beta-galactoside-binding animal lectins, which is implicated in a variety of biological events such as tumor cell adhesion, proliferation, differentiation and angiogenesis. This protein was found to be implicated in cellular transformation and a correlation between its expression and cancer progression and metastasis has been described. The aim of this study was to determine the galectin-3 immunoprofile in 14 cases of ACC (2 cases of tubular subtype, 4 cases of solid subtype and 8 cases of cribriform subtype) and in 12 cases of PLGA with different histologic patterns, including lobular, tubular and cribriform aspects. Moreover, slides of normal salivary glands were included. In normal salivary glands there was strong nuclear and cytoplasmic staining for galectin-3 in ductal luminal cells. ACC showed specific staining in luminal cells mainly in the nuclei. In the tubular subtype of ACC, galectin-3 strongly stained luminal cells of the ductiform structures. The cribriform and solid subtypes showed a few positive luminal cells of small ducts present in the cribriform structures and in solid nests respectively. In the cases of PLGA, independent of the histologic architecture, all tumor cells revealed a positive cytoplasmic reaction. Galectin-3 expression seems to be related to cell differentiation more than to tumor progression and prognosis in the neoplasms studied.

Adult↗

PubMedDate not supplied

Proteomic identification of new biomarkers and application in thyroid cytology.

OBJECTIVE: To validate proteins identified by proteomics as potentially usable markers in thyroid pathology. STUDY DESIGN: Frozen sections of thyroid tumors were manually micro-dissected and proteins extracted. Two-dimensional (2D) gel electrophoresis and subsequent liquid chromatography/mass spectroscopy were performed, and differentially expressed proteins were identified. Validation of candidates for tumor markers (galectin-1, galectin-3, S100C and voltage-dependent anion channel 1 [VDAC1]) was done by immunohistochemistry in 21 cell blocks from fine needle aspiration biopsies (FNAB) and corresponding histology specimens (13 cases). RESULTS: Galectin-3 was negative in benign lesions and positive in FNAB from papillary carcinoma (5 of 5), follicular variant of papillary carcinoma (1 of 4) and follicular carcinoma (1 of 2). S100C was positive in some benign lesions: hyperplasia (2 of 4), goiter (1 of 3) and follicular adenoma (1 of 3), with predominantly nuclear pattern of staining. S100C was positive in malignant lesions, showing cytoplasmic location. Galectin-1 was negative in benign lesions and positive in follicular carcinoma (1 of 2), papillary carcinoma (2 of 5) and follicular variant of papillary carcinoma (1 of 4). VDAC1 was detected in benign and malignant lesions, showing a strong positivity in follicular carcinomas. CONCLUSION: Immunohistochemical validation of potential markers is a crucial step before clinical application in diagnosis. Galectin-3, galectin-1 and S100C can be used to help in discriminating benign and malignant thyroid lesions.

Adenocarcinoma, Follicular↗

PubMed1996

Colon cancer mucin: a new ligand for the beta-galactoside-binding protein galectin-3.

Galectin-3, an endogenous beta-galactoside-binding lectin, is present on colon cancer cells and may play a role in metastasis. Galectin-3 binds poly-N-acetyllactosamine structures on glycoproteins, but its natural ligands remain to be fully defined. Galectin-3 bound to purified native and desialylated colon cancer mucin in a concentration-dependent manner, which was completely inhibited by 0.1 M lactose, the competitive inhibitory sugar for this protein. Mucin purified from highly metastatic LS-Lim6 human colon cancer cells bound galectin-3 to a 2-fold greater extent than mucin from low-metastatic parental cell line LS174T. Desialylation increased binding to mucin >4-fold. Mucin purified from LS-B colon cancer cells is fully glycosylated and bound >40-fold more galectin-3 than mucin purified from clonal cell line LS-C, which produces mucin lacking peripheral carbohydrate structures. Endogenous galectin-3 was detected by Western analysis in all cell lines, and its expression was related to mucin production and metastatic capacity. When serum from a patient with metastatic colorectal cancer was chromatographed on Superose 6, >70% of galectin-3 ligand was identified as circulating mucin. Colon cancer mucin is a newly identified ligand for galectin-3, and binding of galectin-3 to mucins depends on peripheral carbohydrate structures. Binding of this endogenous lectin to mucins; may influence cellular interactions that play a role in colon cancer metastasis.

Adenocarcinoma↗

PubMed2003

Galectin-1 suppresses experimental colitis in mice.

BACKGROUND & AIMS: Uncontrolled T-cell activation plays a critical role in the pathogenesis of inflammatory bowel diseases. Therefore, pharmacologic strategies directed to restore the normal responsiveness of the immune system by deleting inappropriately activated T cells could be efficacious in the treatment of these pathologic conditions. Galectin-1 is an endogenous lectin expressed in lymphoid organs that plays a role in the maintenance of central and peripheral tolerance. The aim of the present study was to evaluate the therapeutic effects of galectin-1 on T-helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. METHODS: Cells and tissues from mice with TNBS colitis receiving treatment with several doses of human recombinant galectin-1 (hrGAL-1) were analyzed for morphology, cytokine production, and apoptosis. RESULTS: Prophylactic and therapeutic administration of rhGAL-1 resulted in a striking improvement in the clinical and histopathologic aspects of the disease. hrGAL-1 reduced the number of hapten-activated spleen T cells, decreased inflammatory cytokine production, and profoundly reduced the ability of lamina propria T cells to produce IFN gamma in vitro. Moreover, hrGAL-1 led to the appearance of apoptotic mononuclear cells in colon tissue when administered in vivo and induced selective apoptosis of TNBS-activated lamina propria T cells in vitro. CONCLUSION: Collectively, these data show that hrGAL-1 exerts protective and immunomodulatory activity in TNBS-induced colitis and it might be effective in the treatment of inflammatory bowel diseases.

Animals↗

PubMed2006

Galectin-1 in secondary alveolar septae of neonatal mouse lung.

In mice, alveolarization occurs during postnatal days 4 through 12, when secondary alveolar septae create thin-walled alveoli in the distal lung. We hypothesized that genes predominantly expressed in newly forming secondary alveolar septae influence the process of alveolarization. To address this hypothesis, tips of secondary alveolar septae were isolated from sections of postnatal day 6 mouse lung tissue using laser capture microdissection. Total RNA was isolated and amplified from the dissected alveolar septal tips and from intact postnatal day 6 lung tissue. Gene expression in the samples was characterized using Affymetrix mouse U74AN2 GeneChips. Galectin-1 was an abundantly expressed transcript that was enriched in the alveolar septal tips compared with levels in the whole lung tissue. Galectins are beta-galactoside-binding proteins involved in the regulation of cell proliferation, differentiation, and apoptosis in fibroblasts, muscle cells and endothelial cells, cell types that are present in the alveolar wall. Immunostaining in postnatal day 6 lung tissue confirmed that galectin-1 protein is concentrated in the tips of secondary alveolar septae, predominantly in myofibroblasts. Fibroblasts isolated from day 6 neonatal mouse lung tissue contained galectin-1 protein. Real-time PCR demonstrated that galectin-1 mRNA levels in mouse lung tissue peak at postnatal day 6. Immunoblot analysis confirmed that peak levels of lung galectin-1 protein are found at postnatal days 6 to 12. The increased expression of galectin-1 at the site and time of ongoing alveolarization in the newborn mouse is suggestive that galectin-1 may play an important role in this critical aspect of lung development.

Aging↗