Role In Intercellular Adhesion Research Articles

Role of CDH23 as a prognostic biomarker and its relationship with immune infiltration in acute myeloid leukemia

BackgroundCadherin-23 (CDH23) plays an important role in intercellular adhesion and is involved in the progression of several types of cancer. However, the biological functions and effect of CDH23 expression on the prognosis of patients with acute myeloid leukemia (AML) are unexplored. Herein, we aim to characterize the role and molecular functions of CDH23 in AML.MethodsWe downloaded the transcriptomic profiles and clinical data from the Cancer Genome Atlas and Beat AML trial. The expression level of CDH23 was assessed using Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier survival analysis was used to assess prognostic value of CDH23. Correlation and biological function analyses were performed using LinkedOmics and GeneMANIA. Relationship of CDH23 with immune infiltration level was determined using Tumor Immune Estimation Resource (TIMER).ResultsWe found that the CDH23 expression was aberrantly upregulated in patients with AML and could be used as an independent risk factor of overall survival using Cox multivariate analysis. Notably, we observed a negative correlation between CDH23 expression and immune cell infiltration abundance by calculating the immune and stromal scores. In addition, functional enrichment analysis established that CDH23 plays a crucial role in tumor immunity.ConclusionsOur findings indicate that upregulated CDH23 expression corresponds to decreased overall survival of patients with AML. CDH23 may be involved in mediating tumor immune environment, and this highlights the potential of CDH23 as a therapeutic target in AML.

Bioproduction, purification, and application of polysialic acid.

Polysialic acid (PSA) is a negatively charged linear homopolymer linked by N-acetylneuraminic acid and widely present in vertebrates and some pathogens. PSA, commonly found on cell surfaces as glycoproteins and glycolipids, plays important roles in intercellular adhesion, cell migration, and formation and remodeling of the neural system by regulating the adhesive property of nerve cell adhesion molecules. PSA with a molecular weight that can reach as high as 260kDa also belongs to the group II capsule polysaccharide of neonatal meningitis-causing Escherichia coli K1. To date, much effort has been devoted to developing the biotechnological production of PSA. As a non-glycosaminoglycan, PSA is a non-immunogenic and biodegradable polysaccharide that can be used as a biomaterial in protein polysialylation, tissue engineering, and drug delivery. PSA can also combine with other macromolecules to form multifunctional composites. In this mini-review, the production, purification, and application of PSA are summarized to provide a basis for further PSA applications.

ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis

ObjectiveAdenomyosis is a benign gynecological disease, characterized by the malignant biological behaviors of invasion and metastasis. ILK plays an important role in intercellular adhesion and triggers the process of EMT. In this study, we investigated the role of ILK-induced EMT in the pathogenesis of adenomyosis. MethodsILK and EMT markers including E-cadherin, N-cadherin and Vimentin have been detected with Immunohistochemistry(IHC), RT-PCR and Western Blot, in normal endometrium, matched eutopic and ectopic endometrium respectively. Primary endometrial cells were isolated in order to observed the morphology features, as well as the change of invasiveness. ResultsHyper-activation of ILK were detected in the adenomyosis lesions, along with the typical aberrant expression of EMT markers. Furthermore, comparing with ESCs, the EuSCs showed a more invasive and dynamic phenotype. ConclusionsILK-induced EMT is a novel mechanism in the pathogenesis of adenomyosis and may be a potential therapeutic agent for adenomyosis.

Paradoxes and wonders of intrinsic disorder: Stability of instability.

This article continues a series of short comments on the paradoxes and wonders of the protein intrinsic disorder phenomenon by introducing the "stability of instability" paradox. Intrinsically disordered proteins (IDPs) are characterized by the lack of stable 3D-structure, and, as a result, have an exceptional ability to sustain exposure to extremely harsh environmental conditions (an illustration of the "you cannot break what is already broken" principle). Extended IDPs are known to possess extreme thermal and acid stability and are able either to keep their functionality under these extreme conditions or to rapidly regain their functionality after returning to the normal conditions. Furthermore, sturdiness of intrinsic disorder and its capability to "ignore" harsh conditions provides some interesting and important advantages to its carriers, at the molecular (e.g., the cell wall-anchored accumulation-associated protein playing a crucial role in intercellular adhesion within the biofilm of Staphylococcus epidermidis), supramolecular (e.g., protein complexes, biologic liquid-liquid phase transitions, and proteinaceous membrane-less organelles), and organismal levels (e.g., the recently popularized case of the microscopic animals, tardigrades, or water bears, that use intrinsically disordered proteins to survive desiccation).

Non-junctional E-Cadherin Clusters Regulate the Actomyosin Cortex in the C. elegans Zygote

Classical cadherins are well known for their essential function in mediating cell-cell adhesion via their extra-cellular cadherin domains and intra-cellular connections to the actin cytoskeleton [1-3]. There is evidence, however, of adhesion-independent cadherin clusters existing outside of cell-cell junctions [4-6]. What function, if any, these clusters have is not known. HMR-1, the sole classical cadherin in Caenorhabditis elegans, plays essential roles during gastrulation, blastomere polarity establishment, and epidermal morphogenesis [7-11]. To elucidate the physiological roles of non-junctional cadherin, we analyzed HMR-1 in the C.elegans zygote, which is devoid of neighbors. We show that non-junctional clusters of HMR-1 form during the one-cell polarization stage and associate with F-actin at the cortex during episodes of cortical flow. Non-junctional HMR-1 clusters downregulate RHO-1 activity and inhibit accumulation of non-muscle myosin II (NMY-2) at the anterior cortex. We found that HMR-1 clusters impede cortical flows and play a role in preserving the integrity of the actomyosin cortex, preventing it from splitting in two. Importantly, we uncovered an inverse relationship between the amount of HMR-1 at the cell surface and the rate of cytokinesis. The effect of HMR-1 clusters on cytokinesis is independent of their effect on NMY-2 levels, and is also independent of their extra-cellular domains. Thus, in addition to their canonical role in inter-cellular adhesion, HMR-1 clusters regulate RHO-1 activity and NMY-2 level at the cell surface, reinforce the stability of the actomyosin cortex, and resist its movement to influence cell-shape dynamics.

Hypotrichosis and juvenile macular dystrophy caused by CDH3 mutation: A candidate disease for retinal gene therapy

Hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder that causes childhood visual impairment. HJMD is caused by mutations in CDH3 which encodes cadherin-3, a protein expressed in retinal pigment epithelium (RPE) cells that may have a key role in intercellular adhesion. We present a case of HJMD and analyse its phenotypic and molecular characteristics to assess the potential for retinal gene therapy as a means of preventing severe visual loss in this condition. Longitudinal in vivo imaging of the retina showed the relative anatomical preservation of the macula, which suggested the presence of a therapeutic window for gene augmentation therapy to preserve visual acuity. The coding sequence of CDH3 fits within the packaging limit of recombinant adeno-associated virus vectors that have been shown to be safe in clinical trials and can efficiently target RPE cells. This report expands the number of reported cases of HJMD and highlights the phenotypic characteristics to consider when selecting candidates for retinal gene therapy.

Proteins Play Important Role in Intercellular Adhesion Affecting on Fruit Textural Quality

Fruit textural quality is becoming a major quality parameter for export, postharvest preservation, handling and processing. The main determinant of textural quality is intercellular adhesion (ICA) as attributed by the cell wall (CW) and its components. The importance of CW protein in ICA strengthening was exemplified in Medjoul date (Phoenix dactylifera L.) fruit, as a model. Fruit mesocarp sensitively responded to culture environment which was assayed in vitro at pH 3.5(< pKa) and pH 6.5(> pKa) in presence of organic acid molecules. The max penetration force, as a measure of ICA strength, of pH 3.5 (< pKa) incubated mesocarp (~10.5 N) was signi cantly higher than that of pH 6.5 (> pKa) incubated fruits (~2 N). The protein bands at ~29 kDa, ~75 kDa, ~32 kDa and 87 kDa were exclusively or prominently found in ICA strengthened fruits (pH 3.5< pKa) compared to texturally injured fruits (pH 6.5 > pKa). DOI: http://dx.doi.org/10.3126/jfstn.v7i0.10564 J. Food Sci. Technol. Nepal, Vol. 7 (31-35), 2012

Association of E-Cadherin Single-Nucleotide Polymorphisms with the Increased Risk of Breast Cancer: A Study in South Indian Women

E-cadherin (CDH1) plays an important role in intercellular adhesion, cell signaling, and cellular differentiation. Association of single-nucleotide polymorphisms (SNPs) of CDH1 has been identified in a number of epithelial malignancies; however, studies related to breast cancer are very few. To investigate the association between CDH1 SNPs and breast cancer risk in south Indian women. Genotyping of CDH1 functional SNPs (-347G/GA, -160C/A, and +54C/T) was carried out on genomic DNA of blood from breast cancer patients (n=202) and controls (n=250) of south Indian origin by PCR-sequencing and PCR-restriction fragment length polymorphism techniques. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview Software. The frequencies of -160A/A genotypes (p=0.038) and -160A alleles (p=0.046) were significantly higher in patients compared to controls. In addition, the frequency of the -347GA/-160A/+54C haplotype was also significantly elevated in patients (p=0.0238). Strong LD was observed between -347G/GA and +54C/T loci (D'=0.44) in patients compared to controls. The CDH1 -160C/A polymorphism may constitute an inheritable risk factor for breast cancer in south Indian women.

The modulatory effect of cell–cell contact on the tumourigenic potential of pre-malignant epithelial cells: a computational exploration

Malignant development cannot be attributed alone to genetic changes in a single cell, but occurs as a result of the complex interplay between the failure of cellular regulation mechanisms and the presence of a permissive microenvironment. Although E-cadherin is classified as a 'metastasis suppressor' owing to its role in intercellular adhesion, the observation that it may be downregulated at a premalignant stage is indicative of additional roles in neoplastic development. We have used an agent-based computational model to explore the emergent behaviour resulting from the interaction of single and subpopulations of E-cadherin-compromised cells with unaffected normal epithelial cells within a monolayer environment. We have extended this to investigate the importance of local tissue perturbations in the form of scratch-wounding, or ablation of randomly-dispersed normal cells, on the growth of a single cell exhibiting E-cadherin loss. Our results suggest that the microenvironment with respect to localized cell density and normal/E-cadherin-compromised neighbours is crucial in determining whether an abnormal individual cell proliferates or remains dormant within the monolayer. These predictions raise important questions relating to the propensity for individual mutations to give rise to disease, and future experimental exploration of these will enhance our understanding of a complex, multifactorial pathological process.

Blood Vessel Epicardial Substance (Bves) Regulates Epidermal Tight Junction Integrity through Atypical Protein Kinase C

Bves is widely observed in the cell junction of the skin, epicardium, intestine, and cornea of both developmental embryos and mature adults. However, it is not clear how Bves confers its role in intercellular adhesion. Here, we identified the zebrafish bves (zBves) and found that the epidermal barrier function could be disrupted after knockdown of Bves, and these zBves morphants were sensitive to osmotic stress. A loss of zBves would affect the partitioning defective protein (PAR) junctional complex identified by the rescue experiment with tjp-2/ZO-2 or the PAR complex (par-3, par-6, and prkci/atypical (a)PKC) mRNAs, in which the survival rate of embryos increased 11, 24, 25, and 28%, respectively, after injection with junctional components; the tjp-2 and aPKC mRNA-rescued embryos also had 24 and 45% decreases in the defective rate. Immunofluorescent studies demonstrated that the aggregation of aPKC around the cell junctions had disintegrated in zBves morphants. However, the expression and assembly of zBves were not influenced by aPKC-MO. These results indicate that a loss of zBves affects the proteins involved in the pathway of the PAR junctional complex, especially aPKC, and both aPKC and Bves are indispensable to claudin expression.

Alteration in E-Cadherin/β-Catenin Expression in Canine Melanotic Tumors

β-Catenin, encoded by the ctnnb1 gene, plays a critical role in intercellular adhesion, and its altered expression has been implicated in tumor progression in humans and animals. The aims of this study were to examine the alterations in β-catenin expression in canine melanoma as well as the causes of these changes (eg, E-cadherin or exon 3 mutations) and to compare identified changes between skin and oral melanomas. Forty-two primary canine skin and oral melanoma tissue samples were used in the study. The expression levels of ctnnb1 and the levels of E-cadherin/β-catenin complex in the tissues were determined by semiquantitative RT-PCR and immunohistochemistry, respectively. The mutational status of β-catenin exon 3 was examined by DNA sequencing. RT-PCR revealed higher levels of ctnnb1 expression in oral melanoma tissues compared with normal melanocytes, irrespective of sex or histopathological appearance of the tissue (ie, amelanotic vs melanotic). Immunohistochemistry revealed simultaneous loss of membrane E-cadherin/β-catenin complex and cytoplasmic accumulation of both proteins in 37 cases (84%). Intranuclear β-catenin was also detected in all tissues with reduced membrane β-catenin expression. In mutational analyses, one amelanotic oral melanoma showed 13 single nucleotide polymorphisms (SNPs); however, after protein translation, all the SNPs were silent mutations. The present study demonstrates that dysregulation of E-cadherin/β-catenin complexes is involved in both types of canine melanotic tumors and that the disruption of E-cadherin/β-catenin complexes and increased β-catenin may induce tumor progression and malignancy.

The Extracellular Architecture of Adherens Junctions Revealed by Crystal Structures of Type I Cadherins

Adherens junctions, which play a central role in intercellular adhesion, comprise clusters of type I classical cadherins that bind via extracellular domains extended from opposing cell surfaces. We show that a molecular layer seen in crystal structures of E- and N-cadherin ectodomains reported here and in a previous C-cadherin structure corresponds to the extracellular architecture of adherens junctions. In all three ectodomain crystals, cadherins dimerize through a trans adhesive interface and are connected by a second, cis, interface. Assemblies formed by E-cadherin ectodomains coated on liposomes also appear to adopt this structure. Fluorescent imaging of junctions formed from wild-type and mutant E-cadherins in cultured cells confirm conclusions derived from structural evidence. Mutations that interfere with the trans interface ablate adhesion, whereas cis interface mutations disrupt stable junction formation. Our observations are consistent with a model for junction assembly involving strong trans and weak cis interactions localized in the ectodomain.

The Na, K-ATPase Beta1 and Beta2 Subunits Associate with Different Quality Control Pathways in the ER

The catalytic Na,K-ATPase α-subunit is not able to exit the ER or catalyze ion transport unless assembled with the β-subunit. However, requirements for the ER exit of the Na,K-ATPase β-subunit that plays an additional, ion-transport-independent, role in intercellular adhesion are not clear. The Na,K-ATPase β1- or β2-subunits and their N-glycosylation-deficient mutants were expressed in renal MDCK cells. Confocal microscopy, immunohistochemistry, and immunoprecipitation were employed to evaluate the role of N-glycans of the β-subunit isoforms in the quality control of the Na,K-ATPase in the ER. Mutagenic removal of as few as two of the eight N-glycosylation sites from the β2-subunit precludes its assembly with the α1 subunit and results in full retention of the unassembled β2-subunit in the ER. However, removal of all three N-glycosylation sites from the β1-subunit only slightly affects its assembly with the α1-subunit and trafficking to the plasma membrane. The β2-subunit binds 4-5-fold more efficiently to the ER lectin chaperone, calnexin, and 2-3-fold less efficiently to the non-lectin ER chaperone, BiP, than the β1-subunit. These results indicate that folding of the β2- and β1-subunits is mediated by lectin and non-lectin chaperones, respectively, consistent with the essential role of N-glycosylation for folding and trafficking of the β2 but not of the β1-subunit. Disruption of the α1-β association by mutations in defined α1-interacting regions of either β1- or β2-subunits results in the ER retention of unassembled mutants, indicating that α-β assembly is essential for the ER export of either β-subunit isoform. In conclusion, the ER quality control system ensures that only properly folded β-subunits assemble with the α-subunits and only assembled α-β complexes are exported to the Golgi and delivered to the plasma membrane.Supported by NIH, DK077149 and DK58333.

Downregulation of N-cadherin Expression Inhibits Invasiveness, Arrests Cell Cycle and Induces Cell Apoptosis in Esophageal Squamous Cell Carcinoma

ABSTRACTSome studies have demonstrated that N-cadherin is upregulated in more invasive cancer cell lines and tumors and plays a key role in intercellular adhesion. However, the understanding on the roles N-cadherin plays in esophageal squamous cell carcinoma (ESCC) is still poor. Our data showed that knock-down of N-cadherin in ESCC cell line (EC9706) could arrest cell cycle at G0/G1 phase, induce cell apoptosis, reduce the invasiveness in vitro, and inhibit the tumor formation in vivo. These results suggest that N-cadherin is an important factor in the progression and metastasis of ESCC and N-cadherin may serve as a potential molecular target for biotherapy of ESCC.

Assembly with the Na,K-ATPase α1 Subunit Is Required for Export of β1 and β2 Subunits from the Endoplasmic Reticulum

The level of the heterodimeric Na,K-ATPase is tightly controlled in epithelia to maintain appropriate transport function. The catalytic Na,K-ATPase alpha subunit is not able to exit the ER or catalyze ion transport unless assembled with the beta subunit. However, requirements for the ER exit of the Na,K-ATPase beta subunit that plays an additional, ion-transport-independent, role in intercellular adhesion are not clear. Exogenous beta(1) or beta(2) subunits expressed in renal MDCK cells replace endogenous beta(1) subunits in the alpha-beta complexes in the ER, resulting in a decrease in the amount of the alpha(1)-bound endogenous beta(1) subunits by 47-61% with no change in the amount of alpha(1) subunits. Disruption of the alpha(1)-beta association by mutations in defined alpha(1)-interacting regions of either beta(1) or beta(2) subunits results in the ER retention and rapid degradation of unassembled mutants. Hence, the ER quality control system allows export only of assembled alpha-beta complexes to the Golgi, thereby maintaining an equimolar ratio of alpha and beta subunits in the plasma membrane, whereas the number of alpha(1) subunits in the ER determines the amount of the alpha-beta complexes.

CEACAM1 : modulateur central du métabolisme, de la progression tumorale,de l’angiogenèse et de l’immunité

CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a member of the immunoglobulin (Ig) superfamily, is a heavily glycosylated protein. This glycoprotein exhibits an intracytoplasmic region that can be either long (71-73 amino acids) with two inhibitory tyrosine-phosphorylated motifs and several phosphorylated serine residues, or short (10 amino acid). CEACAM1 is a multifunctional protein that plays a role in intercellular adhesion, as an inhibitor of tumor development, as a bacterial adhesin, and as a receptor for the mouse hepatitis virus. Moreover, CEACAM1 is an active regulator of cell signaling, modulating the insulin or EGF receptor pathways in epithelial cells or the Zap-70 pathway in hematopoietic cells. The recent development of genetically modified mouse models altering the Ceacam1 gene corroborates most of these data, but also highlights CEACAM1's functional complexity. Thus, in addition to the functions identified previously, CEACAM1 is an important regulator of lipid metabolism, of tumor progression as a regulator of the Wnt signaling pathway, of normal and tumor neo-angiogenesis and of immunity.

β-catenin expression pattern in primary oral squamous cell carcinoma

Beta-catenin, a 92 kDa protein that binds to the cytoplasmic tail of E-cadherin, has an essential role in intercellular adhesion and signal transduction. Aberrant expression of beta-catenin has been associated with progression and metastasis of various human cancers. The aim of this study was to elucidate the expression pattern of beta-catenin in primary oral squamous cell carcinoma and examine the correlation between beta-catenin expression and tumor differentiation, histological grade and lymph node status as well as its clinical significances. Seventy-six patients with oral squamous cell carcinoma and sixteen metastatic lymph nodes were studied. The beta-catenin expression was determined by immunohistochemical staining. The correlation with clinical, histological data was analyzed statistically. Normal oral epithelium showed strong beta-catenin expression at the cell membrane, but no cytoplasmic or nuclear expression. Different degrees of reduced expression of beta-catenin at the cell membrane were found in 54 cases with squamous cell carcinoma (71%). Cytoplasmic beta-catenin expression was found in 17 tumors (22.4%). Three cases were found with nuclear beta-catenin expression. In sixteen lymph nodes with metastatic squamous cell carcinoma, negative beta-catenin expression at the cell membrane was seen in 13 tumors (81.2%) and weak expression in 3 tumors (18.8%). Statistical analysis showed that there was an inverse correlation between beta-catenin expression and lymph node status and histological grade of tumors. Reduced beta-catenin expression at the cell membrane is clearly associated with lymph node metastasis. A reduced expression of beta-catenin may constitute a hallmark of aggressive biological behavior of squamous cell carcinoma.

IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells

Invasion and metastases of cancer cells are the main causes of treatment failure in cancer. IQ motif-containing GTPase activating protein 1 (IQGAP1), plays pivotal roles in intercellular adhesion, migration, invasion and metastases in various cancer cells. However, the role of another family member, IQGAP2, in carcinogenesis remains unknown. Here, we investigated IQGAP2 functions in gastric cancers. We found that IQGAP2 protein expression was lost in 5 of the 9 gastric cancer cell lines. Through analysis by the methylation-specific PCR, aberrant IQGAP2 methylation was detected in 3 gastric cancer cell lines. IQGAP2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. Moreover, IQGAP2 methylation was detected in 28 of the 59 (47%) primary gastric cancer tissues, but not in 12 normal gastric mucosa samples. Immunohistochemical staining revealed that 7 of the 8 (88%) gastric cancer tissues without methylation signals displayed IQGAP2 expression, whereas among 10 with methylation signals none expressed IQGAP2 (p = 0.0002), indicating that IQGAP2 methylation is highly associated with loss of the IQGAP2 expression in the primary gastric cancer tissues as well as gastric cancer cell lines. Furthermore, IQGAP2 methylation was also associated with tumor invasion and a poor prognosis. IQGAP2 knockdown with small interfering RNA increased the invasive capacity of a gastric cancer cell line. These results suggest that silencing of IQGAP2 by promoter methylation may contribute to gastric cancer development.

The biological role of death and lysis in biofilm development

Recent studies have revealed that the regulated death of bacterial cells is important for biofilm development. Following cell death, a sub-population of the dead bacteria lyse and release genomic DNA, which then has an essential role in intercellular adhesion and biofilm stability. This Opinion focuses on the role of regulated cell death and lysis in biofilm development and provides a functional comparison between bacterial programmed cell death and apoptosis. The hypothesis that the differential regulation of these processes during biofilm development contributes to the antibiotic tolerance of biofilm cells is also explored.

Expression of E-cadherin, P-cadherin and β-catenin in canine malignant mammary tumours in relation to clinicopathological parameters, proliferation and survival

Cadherin–catenin complexes play a critical role in intercellular adhesion, and their altered expression has been implicated in tumour progression. In this study, the expression of E-cadherin, P-cadherin and β-catenin was analysed in 65 canine malignant mammary tumours and correlated with clinicopathological parameters, proliferation and survival. Reduction in E-cadherin expression was significantly associated with increased tumour size, high histological and invasion grades, lymph node metastasis and high mitotic index. Reduced β-catenin expression was associated with high histological and invasion grades. Anomalous expression of P-cadherin was only associated with invasion. In 39 cases for which follow-up data were available, reduced E-cadherin and β-catenin expression was significantly associated with shorter overall survival and disease free survival. Abnormal expression of adhesion molecules is a common phenomenon in canine mammary malignant tumours and may play a central role in tumour progression.