eNOS Regulates Lymphatic Valve Specification by Controlling ß-Catenin Signaling During Embryogenesis in Mice.

BACKGROUND: Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (endothelial NO synthase; gene name: Nos3) is a well-characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. METHODS: We used global Nos3-/- mice and cultured human dermal lymphatic endothelial cells to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. RESULTS: Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of ß-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of ß-catenin target proteins in vivo and in vitro. However, pharmacological inhibition of NO production did not reproduce these effects. Co-immunoprecipitation and proximity ligation assays reveal that eNOS directly binds to ß-catenin and their binding is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and partially rescued the loss of valve specification in the eNOS knockouts. CONCLUSIONS: In conclusion, we demonstrate a novel, NO-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS directly binds ß-catenin to regulate its nuclear translocation and thereby transcriptional activity.

Sorting of cadherin-catenin-associated proteins into individual clusters.

The cytoplasmic tails of classical cadherins form a multiprotein cadherin-catenin complex (CCC) that constitutes the major structural unit of adherens junctions (AJs). The CCC in AJs forms junctional clusters, "E clusters," driven by cis and trans interactions in the cadherin ectodomain and stabilized by α-catenin-actin interactions. Additional proteins are known to bind to the cytoplasmic region of the CCC. Here, we analyze how these CCC-associated proteins (CAPs) integrate into cadherin clusters and how they affect the clustering process. Using a cross-linking approach coupled with mass spectrometry, we found that the majority of CAPs, including the force-sensing protein vinculin, interact with CCCs outside of AJs. Accordingly, structural modeling shows that there is not enough space for CAPs the size of vinculin to integrate into E clusters. Using two CAPs, scribble and erbin, as examples, we provide evidence that these proteins form separate clusters, which we term "C clusters." As proof of principle, we show, by using cadherin ectodomain monoclonal antibodies (mAbs), that mAb-bound E-cadherin forms separate clusters that undergo trans interactions. Taken together, our data suggest that, in addition to its role in cell-cell adhesion, CAP-driven CCC clustering serves to organize cytoplasmic proteins into distinct domains that may synchronize signaling networks of neighboring cells within tissues.

[E-cadherin: structure and functions, role in gastric cancer carcinogenesis]. / E-kadgerin: stroenie i funktsii, rol' v kantserogeneze raka zheludka.

This review is dedicated to E-cadherin, a calcium-dependent cell-cell adhesion molecule with pivotal roles in epithelial cell behavior, tissue formation, and carcinogenesis. We summarize the structure of the E-cadherin, its role in the development of the body and in the carcinogenesis. The structure of the E-cadherin/ß-catenin/αE-catenin complex and its relationship with the actin cytoskeleton are described in detail. The role of E-cadherin in the development of some infectious diseases, the function of E-cadherin as both a tumor suppressor and a promoter of tumor dissemination, its influence on signal transduction pathways in cells are highlighted. Particular attention is paid to the expression of E-cadherin in Helicobacter pylori infection and in tumor tissue in gastric cancer.

Yes-associated protein activation potentiates glycogen synthase kinase-3 inhibitor-induced proliferation of neonatal cardiomyocytes and iPS cell-derived cardiomyocytes.

Because mammalian cardiomyocytes largely cease to proliferate immediately after birth, the regenerative activity of the heart is limited. To date, much effort has been made to clarify the regulatory mechanism of cardiomyocyte proliferation because the amplification of cardiomyocytes could be a promising strategy for heart regenerative therapy. Recently, it was reported that the inhibition of glycogen synthase kinase (GSK)-3 promotes the proliferation of neonatal rat cardiomyocytes (NRCMs) and human iPS cell-derived cardiomyocytes (hiPSC-CMs). Additionally, Yes-associated protein (YAP) induces cardiomyocyte proliferation. The purpose of this study was to address the importance of YAP activity in cardiomyocyte proliferation induced by GSK-3 inhibitors (GSK-3Is) to develop a novel strategy for cardiomyocyte amplification. Immunofluorescent microscopic analysis using an anti-Ki-67 antibody demonstrated that the treatment of NRCMs with GSK-3Is, such as BIO and CHIR99021, increased the ratio of proliferative cardiomyocytes. YAP was localized in the nuclei of more than 95% of cardiomyocytes, either in the presence or absence of GSK-3Is, indicating that YAP was endogenously activated. GSK-3Is increased the expression of ß-catenin and promoted its translocation into the nucleus without influencing YAP activity. The knockdown of YAP using siRNA or pharmacological inhibition of YAP using verteporfin or CIL56 dramatically reduced GSK-3I-induced cardiomyocyte proliferation without suppressing ß-catenin activation. Interestingly, the inhibition of GSK-3 also induced the proliferation of hiPSC-CMs under sparse culture conditions, where YAP was constitutively activated. In contrast, under dense culture conditions, in which YAP activity was suppressed, the proliferative effects of GSK-3Is on hiPSC-CMs were not detected. Importantly, the activation of YAP by the knockdown of α-catenin restored the proproliferative activity of GSK-3Is. Collectively, YAP activation potentiates the GSK-3I-induced proliferation of cardiomyocytes. The blockade of GSK-3 in combination with YAP activation resulted in remarkable amplification of cardiomyocytes.

Wnt-C59 inhibits proinflammatory cytokine expression by reducing the interaction between ß-catenin and NF-κB in LPS-stimulated epithelial and macrophage cells.

Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson's disease, Alzheimer's disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/ß-catenin pathway in LPS stimulated cells was suppressed by Wnt- C59 treatment. The level of ß-catenin, the executor protein of Wnt/ß-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of ß-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between ß-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between ß-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of ß-catenin and the interaction between ß-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.

New MRI features improve subtype classification of hepatocellular adenoma.

OBJECTIVE: MRI is crucial for the classification of hepatocellular adenomas (HCA) into subtypes. Our objective was to review and increase MRI criteria for subtype classification and define the limits. METHODS: Pathological and radiological data of 116 HCAs were retrospectively analyzed to investigate MRI features of HCA pathological subtypes. Risk for complication was also evaluated with regard to subtype and tumor size. RESULTS: 38/43 (88%) HNF1α-mutated HCAs (H-HCAs) were discriminated by (i) fatty component (homogeneous or heterogeneous) and (ii) hypovascular pattern, with a sensitivity of 88% and a specificity of 97%. 51/58 (88%) inflammatory HCAs (IHCAs) displayed features of sinusoidal dilatation (SD) including three different patterns (global SD, atoll sign, and a new "crescent sign" corresponding to a partial peripheral rim, hyperintense on T2W and/or arterial phase with persistent delayed enhancement). Sensitivity was 88% and specificity 100%. However, some HCA remained unclassifiable by MRI: HCA remodeled by necrotic/hemorrhagic changes covering > 50% of the lesion, H-HCAs without steatosis, IHCAs without SD, ß-catenin-mutated and unclassified HCAs. Regarding malignant transformation (5/116) and bleeding (24/116), none was observed when the HCA diameter was smaller than 5.2 cm and 4.2 cm, respectively. CONCLUSION: Based on the largest series evaluated until now, we identified several non-described MRI features and propose new highly sensitive and specific MRI criteria. With the addition of these new features, 88% of the two main HCA subtypes could be identified. KEY POINTS: • HNF1α-mutated hepatocellular adenomas (H-HCA) are characterized by the presence of fat and hypovascular pattern in MRI. • Inflammatory hepatocellular adenomas (I-HCA) are characterized by different patterns translating sinusoidal dilatation including the newly described crescent sign. • No MRI specific pattern was identified for ß-catenin-mutated HCA (b-HCA).

Evolution and diversity of cadherins and catenins.

Cadherin genes encode a superfamily of conserved transmembrane proteins that share an adhesive ectodomain composed of tandem cadherin repeats. More than 100 human cadherin superfamily members have been identified, which can be classified into three families: major cadherins, protocadherins and cadherin-related proteins. These superfamily members are involved in diverse fundamental cellular processes including cell-cell adhesion, morphogenesis, cell recognition and signaling. Epithelial cadherin (E-cadherin) is the founding cadherin family member. Its cytoplasmic tail interacts with the armadillo catenins, p120 and ß-catenin. Further, α-catenin links the cadherin/armadillo catenin complex to the actin filament network. Even genomes of ancestral metazoan species such as cnidarians and placozoans encode a limited number of distinct cadherins and catenins, emphasizing the conservation and functional importance of these gene families. Moreover, a large expansion of the cadherin and catenin families coincides with the emergence of vertebrates and reflects a major functional diversification in higher metazoans. Here, we revisit and review the functions, phylogenetic classifications and co-evolution of the cadherin and catenin protein families.

Metazoan evolution of the armadillo repeat superfamily.

The superfamily of armadillo repeat proteins is a fascinating archetype of modular-binding proteins involved in various fundamental cellular processes, including cell-cell adhesion, cytoskeletal organization, nuclear import, and molecular signaling. Despite their diverse functions, they all share tandem armadillo (ARM) repeats, which stack together to form a conserved three-dimensional structure. This superhelical armadillo structure enables them to interact with distinct partners by wrapping around them. Despite the important functional roles of this superfamily, a comprehensive analysis of the composition, classification, and phylogeny of this protein superfamily has not been reported. Furthermore, relatively little is known about a subset of ARM proteins, and some of the current annotations of armadillo repeats are incomplete or incorrect, often due to high similarity with HEAT repeats. We identified the entire armadillo repeat superfamily repertoire in the human genome, annotated each armadillo repeat, and performed an extensive evolutionary analysis of the armadillo repeat proteins in both metazoan and premetazoan species. Phylogenetic analyses of the superfamily classified them into several discrete branches with members showing significant sequence homology, and often also related functions. Interestingly, the phylogenetic structure of the superfamily revealed that about 30 % of the members predate metazoans and represent an ancient subset, which is gradually evolving to acquire complex and highly diverse functions.

Role of cell-cell adhesion complexes in embryonic stem cell biology.

Pluripotent embryonic stem cells (ESCs) can self-renew or differentiate into any cell type within an organism. Here, we focus on the roles of cadherins and catenins - their cytoplasmic scaffold proteins - in the fate, maintenance and differentiation of mammalian ESCs. E-cadherin is a master stem cell regulator that is required for both mouse ESC (mESC) maintenance and differentiation. E-cadherin interacts with key components of the naive stemness pathway and ablating it prevents stem cells from forming well-differentiated teratomas or contributing to chimeric animals. In addition, depleting E-cadherin converts naive mouse ESCs into primed epiblast-like stem cells (EpiSCs). In line with this, a mesenchymal-to-epithelial transition (MET) occurs during reprogramming of somatic cells towards induced pluripotent stem cells (iPSCs), leading to downregulation of N-cadherin and acquisition of high E-cadherin levels. ß-catenin exerts a dual function; it acts in cadherin-based adhesion and in WNT signaling and, although WNT signaling is important for stemness, the adhesive function of ß-catenin might be crucial for maintaining the naive state of stem cells. In addition, evidence is rising that other junctional proteins are also important in ESC biology. Thus, precisely regulated levels and activities of several junctional proteins, in particular E-cadherin, safeguard naive pluripotency and are a prerequisite for complete somatic cell reprogramming.

Migratory neural crest cell αN-catenin impacts chick trigeminal ganglia formation.

Neural crest cells are an embryonic cell population that is crucial for proper vertebrate development. Initially localized to the dorsal neural folds, premigratory neural crest cells undergo an epithelial-to-mesenchymal transition (EMT) and migrate to their final destinations in the developing embryo. Together with epidermally-derived placode cells, neural crest cells then form the cranial sensory ganglia of the peripheral nervous system. Our prior work has shown that αN-catenin, the neural subtype of the adherens junction α-catenin protein, regulates cranial neural crest cell EMT by controlling premigratory neural crest cell cadherin levels. Although αN-catenin down-regulation is critical for initial neural crest cell EMT, a potential role for αN-catenin in later neural crest cell migration, and formation of the cranial ganglia, has not been examined. In this study, we show for the first time that migratory neural crest cells that will give rise to the cranial trigeminal ganglia express αN-catenin and Cadherin-7. αN-catenin loss- and gain-of-function experiments reveal effects on the migratory neural crest cell population that include subsequent defects in trigeminal ganglia assembly. Moreover, αN-catenin perturbation in neural crest cells impacts the placode cell contribution to the trigeminal ganglia and also changes neural crest cell Cadherin-7 levels and localization. Together, these results highlight a novel function for αN-catenin in migratory neural crest cells that form the trigeminal ganglia.

N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo.

N-Cadherin and ß-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, ß-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N-cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N-cadherin/ß-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function.

Paraquat and Parkinson's Disease: The Molecular Crosstalk of Upstream Signal Transduction Pathways Leading to Apoptosis.

Parkinson's disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/ß-catenin signaling pathways.

Evolution and cell physiology. 3. Using Dictyostelium discoideum to investigate mechanisms of epithelial polarity.

In Metazoa, a polarized epithelium forms a single-cell-layered barrier that separates the outside from the inside of the organism. In tubular epithelia, the apical side of the cell is constricted relative to the basal side, forming a wedge-shaped cell that can pack into a tube. Apical constriction is mediated by actomyosin activity. In higher animals, apical actomyosin is connected between cells by specialized cell-cell junctions that contain a classical cadherin, the Wnt signaling protein ß-catenin, and the actin-binding protein α-catenin. The molecular mechanisms that lead to selective accumulation of myosin at the apical surface of cells are poorly understood. We found that the nonmetazoan Dictyostelium discoideum forms a polarized epithelium that surrounds the stalk tube at the tip of the multicellular fruiting body. Although D. discoideum lacks a cadherin homolog, it expresses homologs of ß- and α-catenin. Both catenins are essential for formation of the tip epithelium, polarized protein secretion, and proper multicellular morphogenesis. Myosin localizes apically in tip epithelial cells, and it appears that constriction of this epithelial tube is required for proper morphogenesis. Localization of myosin II is controlled by the protein IQGAP1 and its binding partners cortexillins I and II, which function downstream of α- and ß-catenin to exclude myosin from the basolateral cortex and promote apical accumulation of myosin. These studies show that the function of catenins in cell polarity predates the evolution of Wnt signaling and classical cadherins, and that apical localization of myosin is a morphogenetic mechanism conserved from nonmetazoans to vertebrates.

Adherens junction: the ensemble of specialized cadherin clusters.

The cell-cell connections in adherens junctions (AJs) are mediated by transmembrane receptors, type I cadherins (referred to here as cadherins). These cadherin-based connections (or trans bonds) are weak. To upregulate their strength, cadherins exploit avidity, the increased affinity of binding between cadherin clusters compared with isolated monomers. Formation of such clusters is a unique molecular process that is driven by a synergy of direct and indirect cis interactions between cadherins located at the same cell. In addition to their role in adhesion, cadherin clusters provide structural scaffolds for cytosolic proteins, which implicate cadherin into different cellular activities and signaling pathways. The cluster lifetime, which depends on the actin cytoskeleton, and on the mechanical forces it generates, determines the strength of AJs and their plasticity. The key aspects of cadherin adhesion, therefore, cannot be understood at the level of isolated cadherin molecules, but should be discussed in the context of cadherin clusters.

Catenin signaling controls phrenic motor neuron development and function during a narrow temporal window.

Phrenic Motor Column (PMC) neurons are a specialized subset of motor neurons (MNs) that provide the only motor innervation to the diaphragm muscle and are therefore essential for survival. Despite their critical role, the mechanisms that control phrenic MN development and function are not well understood. Here, we show that catenin-mediated cadherin adhesive function is required for multiple aspects of phrenic MN development. Deletion of ß- and γ-catenin from MN progenitors results in perinatal lethality and a severe reduction in phrenic MN bursting activity. In the absence of catenin signaling, phrenic MN topography is eroded, MN clustering is lost and phrenic axons and dendrites fail to grow appropriately. Despite the essential requirement for catenins in early phrenic MN development, they appear to be dispensable for phrenic MN maintenance, as catenin deletion from postmitotic MNs does not impact phrenic MN topography or function. Our data reveal a fundamental role for catenins in PMC development and suggest that distinct mechanisms are likely to control PMC maintenance.

Evaluating the Role of Hepatobiliary Phase of Gadoxetic Acid-Enhanced Magnetic Resonance Imaging in Predicting Treatment Impact of Lenvatinib and Atezolizumab plus Bevacizumab on Unresectable Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab therapy has high response rates in patients with unresectable hepatocellular carcinoma (HCC). The hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) has been reported to be useful as an imaging biomarker for detecting ß-catenin mutations. We evaluated whether the pretreatment of the hepatobiliary phase of EOB-MRI could predict the therapeutic effect of lenvatinib and atezolizumab plus bevacizumab. METHODS: This study included 68 patients (lenvatinib group (n = 33) and atezolizumab plus bevacizumab group (n = 35)). The visual assessment and relative enhancement ratio (RER) of the largest HCC lesions were evaluated using the hepatobiliary phase of EOB-MRI. RESULTS: The hyperintensity type (RER ≥ 0.9) was 18.2% in the lenvatinib group and 20.0% in the atezolizumab plus bevacizumab group. In the lenvatinib group, progression-free survival (PFS) was not different between the heterogeneous and homogenous types (p = 0.688) or between the hyperintensity and hypointensity types (p = 0.757). In the atezolizumab plus bevacizumab group, the heterogeneous type had significantly shorter PFS than the homogenous type (p = 0.007), and the hyperintensity type had significantly shorter PFS than the hypointensity type (p = 0.012). CONCLUSIONS: The hepatobiliary phase of EOB-MRI was useful for predicting the therapeutic effect of atezolizumab plus bevacizumab therapy on unresectable HCC.

Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases.

The function and structure of the mammalian epithelial cell layer is maintained by distinct intercellular adhesion complexes including adherens junctions (AJs), tight junctions, and desmosomes. The AJ is most integral for stabilizing cell-cell adhesion and conserving the structural integrity of epithelial tissues. AJs are comprised of the transmembrane protein E-cadherin and cytoplasmic catenin cofactors (α, ß, γ, and p120-catenin). One organ where malfunction of AJ is a major contributor to disease states is the mammalian intestine. In the intestine, cell-cell adhesion complexes work synergistically to maintain structural integrity and homeostasis of the epithelium and prevent its malfunction. Consequently, when AJ integrity is compromised in the intestinal epithelium, the ensuing homeostatic disruption leads to diseases such as inflammatory bowel disease and colorectal carcinoma. In addition to their function at the plasma membrane, protein components of AJs also have nuclear functions and are thus implicated in regulating gene expression and intracellular signaling. Within the nucleus, AJ proteins have been shown to interact with transcription factors such as TCF/LEF and Kaiso (ZBTB33), which converge on the canonical Wnt signaling pathway. The multifaceted nature of AJ proteins highlights their complexity in modulating homeostasis and emphasizes the importance of their subcellular localization and expression in the mammalian intestine. In this review, we summarize the nuclear roles of AJ proteins in intestinal tissues; their interactions with transcription factors and how this leads to crosstalk with canonical Wnt signaling; and how nuclear AJ proteins are implicated in intestinal homeostasis and disease.

Co-administration of 5FU and propolis on AOM/DSS induced colorectal cancer in BALB-c mice.

AIMS: Currently, the main problems with chemotherapy are its side effects, toxicity, and drug resistance. Propolis has biological activities, such as anti-inflammatory and anti-cancer properties. This study aims to examine the combined effects of 5-fluorouracil (5FU) and propolis on colorectal cancer (CRC) in mouse models. MATERIALS AND METHODS: The chemical composition of ethanolic extract of propolis was determined by gas chromatography-mass spectrometry (GC-MS). In this study, 49 male Balb/c mice (16-20 g) were divided in seven groups as a control group and experimental groups (treated and untreated CRC model [azoxymethane + dextran sodium sulfate]). This study was conducted in 8 weeks. To examine the anti-cancer effects of propolis, the number of aberrant crypt foci (ACF) was counted and the pathological lesions in the distal colonic epithelial tissue were diagnosed. In this study, the expression of beta-catenin (ß-catenin), induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins, which play a major role in the incidence and progression of cancer, were determined. KEY FINDINGS: GC-MS analysis of propolis showed the presence of hydrocarbons, alcohols, ketones, terpenes, phenols, and flavonoids. Administering propolis in combination with 5FU reduced the number of ACFs and pathological lesions in comparison with cancer control groups (p < 0.0001) and 5FU-alone treatment (p < 0.05). The propolis combined with 5FU reduced the expression of Cox-2, iNOS, and ß-catenin proteins. SIGNIFICANCE: The results showed that propolis increased the efficiency of 5FU and could be taken into account as the adjunct therapy for colorectal cancer.

α-catenin, ß-catenin and P-120-catenin immunoexpression in canine mammary tissues and their relationship with E-cadherin.

Mammary tumors represent the second most common neoplasia in the canine species, where more than 50% of the cases are classified as malignant. The histological classification is used as a prognostic tool. Cadherins and catenins are responsible for cell adhesion and are intrinsic connected with the process of metastasis. E-cadherin expression in canine mammary tissues have been extensively studied. However, the studies with catenins are still scarce in the canine species. This study evaluated 74 canine mammary tissues by assessing the expression of E-cadherin and α, ß and P-120 catenin molecules using the immunohistochemistry technique and their relationship with clinicopathological parameters. Three patterns of expression were identified in this study: membranous, cytoplasmic and both (membranous and cytoplasmic). In benign tumors, more than 80% of the cases had preserved expression and in malignant tumors 20% of the cases had reduced expression. A correlation between E-cadherin and P-120-catenin expression was found as well as a significant relationship between the histological type and the expression of α-catenin in malignant tumors.

Cell adhesion molecules in endometrial cancer - A systematic review.

Adhesive molecules are responsible for the cell-cell interaction and the surrounding intercellular environment creating normal tissue architecture. The role of adhesion proteins in cancer refers to angiogenesis, loss of tissue continuity, and deprivation of intercellular contact with the extracellular matrix, promoting the spread of cancer through the formation of metastases. The integrity of the epithelium is disturbed - with disturbances in the whole mechanism of cell connections, thanks to which cancer cells infiltrate surrounding tissues, and move to lymphatic and blood vessels. Adhesive molecules are divided into five main families: cadherin, catenins, integrins, the immunoglobulin superfamily and non-classical adhesion molecules. In the present review we describe the role of all five families of adhesive molecules in endometrial cancer.