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Breast cancer (BRCA) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers expressed during estradiol and tamoxifen treatment of BRCA. The microarray dataset of E-MTAB-4975 from Array Express database was downloaded, and the differential expressed genes (DEGs) between estradiol-treated BRCA sample and tamoxifen-treated BRCA sample were identified by limma package. The pathway and gene ontology (GO) enrichment analysis, construction of protein-protein interaction (PPI) network, module analysis, construction of target genes—miRNA interaction network and target genes-transcription factor (TF) interaction network were performed using bioinformatics tools. The expression, prognostic values, and mutation of hub genes were validated by SurvExpress database, cBioPortal, and human protein atlas (HPA) database. A total of 856 genes (421 up-regulated genes and 435 down-regulated genes) were identified in T47D (overexpressing Split Ends (SPEN) + estradiol) samples compared to T47D (overexpressing Split Ends (SPEN) + tamoxifen) samples. Pathway and GO enrichment analysis revealed that the DEGs were mainly enriched in response to lysine degradation II (pipecolate pathway), cholesterol biosynthesis pathway, cell cycle pathway, and response to cytokine pathway. DEGs (MCM2, TCF4, OLR1, HSPA5, MAP1LC3B, SQSTM1, NEU1, HIST1H1B, RAD51, RFC3, MCM10, ISG15, TNFRSF10B, GBP2, IGFBP5, SOD2, DHF and MT1H), which were significantly up- and down-regulated in estradiol and tamoxifen-treated BRCA samples, were selected as hub genes according to the results of protein-protein interaction (PPI) network, module analysis, target genes—miRNA interaction network and target genes-TF interaction network analysis. The SurvExpress database, cBioPortal, and Human Protein Atlas (HPA) database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. A comprehensive bioinformatics analysis was performed, and potential therapeutic applications of estradiol and tamoxifen were predicted in BRCA samples. The data may unravel the future molecular mechanisms of BRCA. [ABSTRACT FROM AUTHOR]

Gap junction proteins are expressed in cancer stem cells and non-stem cancer cells of many tumors. As the morphology and assembly of gap junction channels are crucial for their function in intercellular communication, one focus of our review is to outline the data on gap junction plaque morphology available for cancer cells. Electron microscopic studies and freeze-fracture analyses on gap junction ultrastructure in cancer are summarized. As the presence of gap junctions is relevant in solid tumors, we exemplarily outline their role in glioblastomas and in breast cancer. These were also shown to contain cancer stem cells, which are an essential cause of tumor onset and of tumor transmission into metastases. For these processes, gap junctional communication was shown to be important and thus we summarize, how the expression of gap junction proteins and the resulting communication between cancer stem cells and their surrounding cells contributes to the dissemination of cancer stem cells via blood or lymphatic vessels. Based on their importance for tumors and metastases, future cancer-specific therapies are expected to address gap junction proteins. In turn, gap junctions also seem to contribute to the unattainability of cancer stem cells by certain treatments and might thus contribute to therapeutic resistance. [ABSTRACT FROM AUTHOR]

Neuron glial antigen 2 (NG2) is a chondroitin sulphate proteoglycan 4 (CSPG4) that occurs in developing and adult central nervous systems (CNSs) as a marker of oligodendrocyte precursor cells (OPCs) together with platelet-derived growth factor receptor α (PDGFRα). It behaves variably in different pathological conditions, and is possibly involved in the origin and progression of human gliomas. In the latter, NG2/CSPG4 induces cell proliferation and migration, is highly expressed in pericytes, and plays a role in neoangiogenesis. NG2/CSPG4 expression has been demonstrated in oligodendrogliomas, astrocytomas, and glioblastomas (GB), and it correlates with malignancy. In rat tumors transplacentally induced by N-ethyl-N-nitrosourea (ENU), NG2/CSPG4 expression correlates with PDGFRα, Olig2, Sox10, and Nkx2.2, and with new vessel formation. In this review, we attempt to summarize the normal and pathogenic functions of NG2/CSPG4, as well as its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Glycosaminoglycan-modified proteoglycans play important roles in many cell activities, including cell differentiation and stem cell development. Tumor sphere formation ability is one of properties in cancer stem cells (CSCs). The correlation between CSC markers and proteoglycan remains to be clarified. Upon hepatoma sphere formation, expression of CSC markers CD13, CD90, CD133, and CD44, as well the syndecan family protein syndecan-1 (SDC1), increased as analyzed by PCR. Further examination by suppression of CD13 expression showed downregulation of SDC1 and CD44 gene expression, whereas suppression of SDC1 gene expression downregulated CD13 and CD44 gene expression. Suppression of SDC1 gene expression also suppressed sphere development, as analyzed by a novel sphereocrit assay to quantify the level of sphere formation. The heparin disaccharide components, but not those of chondroitin disaccharide, changed with hepatoma sphere development, revealing the increased levels of N-sulfation and 2-O-sulfation. These explained the inhibition of hepatoma sphere formation by exogenous heparin. In conclusion, we found that SDC1 affected CSC marker CD13 and CD44 expression. SDC1 proteoglycan and heparin components changed and affected hepatoma sphere development. Application of heparin mimics in reduction of hepatoma stem cells might be possible. Key words: glycosaminoglycans, cancer stem-like cells, heparan sulfate proteoglycans, disaccharide composition analysis. Les protéoglycanes modifiés par des glycosaminoglycanes jouent des rôles importants dans plusieurs activités cellulaires, dont la différenciation cellulaire et le développement des cellules souches. La capacité de formation de sphères tumorales constitue une des propriétés des cellules souches cancéreuses (CSC). La corrélation entre l'expression de marqueurs des CSC et les protéoglycanes reste à être clarifiée. À la suite de la formation de sphères d'hépatome, l'expression des marqueurs de CSC CD13, CD90, CD133 et CD44, de même que de celle de la protéine syndécane-1 (SDC1), membre de la famille des syndécanes, était accrue selon l'analyse par PCR. Un examen supplémentaire de la suppression de l'expression du CD13 montrait une régulation à la baisse de l'expression génique de la SDC1 et du CD44, alors que la suppression de l'expression génique de la SDC1 régulait à la baisse l'expression génique du CD13 et du CD44. La suppression de l'expression génique de la SDC1 réprimait aussi le développement des sphères, tel qu'analysé par un nouveau dosage, le sphérocrite, qui quantifie le niveau de formation de sphères. Les disaccharides d'héparine, contrairement aux disaccharides de chondroïtine, changeaient en fonction du développement des sphères, révélant des niveaux accrus de N-sulfation et de 2-O-sulfation. Cela expliquait l'inhibition de la formation des sphères d'hépatome par de l'héparine exogène. En conclusion, les auteurs ont trouvé que la SDC1 affectait l'expression des marqueurs de CSC CD13 et CD44. Les protéoglycanes et les composantes d'héparine changeaient et affectaient le développement de sphères d'hépatome. L'application d'un mime d'héparine afin de réduire les cellules souches d'hépatome pourrait avoir un potentiel. [Traduit par la Rédaction] Mots-clés : glycosaminoglycanes, cellules cancéreuses de type cellules souches, protéoglycanes de sulfate d'héparane, analyse de composition des disaccharides., Introduction Hepatocellular carcinoma is primary liver malignancy with low prognosis and high reoccurrence. It was accepted that the presence of cancer stem cells (CSCs) makes tumors difficult to detect and [...]

Myeloperoxidase (MPO) is an oxidant-producing enzyme that can also regulate cellular functions via its nonenzymatic effects. Mature active MPO isolated from normal human neutrophils is a 145 kDa homodimer, which consists of 2 identical protomers, connected by a single disulfide bond. By binding to CD11b/CD18 integrin, dimeric MPO induces neutrophil activation and adhesion augmenting leukocyte accumulation at sites of inflammation. This study was performed to compare the potency of dimeric and monomeric MPO to elicit selected neutrophil responses. Monomeric MPO (hemi-MPO) was obtained by treating the dimeric MPO by reductive alkylation. Analysis of the crucial signal transducer, intracellular [Ca.sup.2+], showed that dimeric MPO induces [Ca.sup.2+] mobilization from the intracellular calcium stores of neutrophils and influx of extracellular [Ca.sup.2+] whereas the effect of monomeric MPO on [Ca.sup.2+] increase in neutrophils was less. It was also shown that monomeric MPO was less efficient than dimeric MPO at inducing actin cytoskeleton reorganization, cell survival, and neutrophil degranulation. Furthermore, we have detected monomeric MPO in the blood plasma of patients with acute inflammation. Our data suggest that the decomposition of dimeric MPO into monomers can serve as a regulatory mechanism that controls MPO-dependent activation of neutrophils and reduces the proinflammatory effects of MPO. Key words: monomeric myeloperoxidase, dimeric myeloperoxidase, inflammation, neutrophils, oxidative/halogenative stress. La myeloperoxydase (MPO) est une enzyme generant des composes oxydants qui peut aussi reguler la fonction des cellules immunitaires et non immunitaires par ses effets non enzymatiques. La MPO active mature isolee des neutrophiles humain normaux est un homodimere de 145 kDa, qui consiste en 2 protomeres identiques, joints par un seul pont disulfure. En se liant a l'integrine CD11b/CD18, la MPO dimere induit l'activation et l'adhesion des neutrophiles, accroissant l'accumulation de ces leucocytes aux sites inflammatoires. Cette etude a ete realisee pour comparer le pouvoir de la MPO sous formes dimere et monomere a provoquer des reponses selectionnees chez le neutrophile. La MPO monomere (hemi-MPO) a ete obtenue en soumettant la MPO dimere a une alkylation reductrice. L'analyse du signal de transduction essentiel, le [Ca.sup.2+] intracellulaire, montrait que la MPO dimere induisait la mobilisation de [Ca.sup.2+] des reserves intracellulaires des neutrophiles et un influx de [Ca.sup.2+] extracellulaire, alors que l'effet de la MPO monomere sur le [Ca.sup.2+] etait moindre. Il s'averait que la MPO monomere etait moins efficace que la MPO dimere a induire la reorganisation du cytosquelette d'actine, la survie cellulaire et la degranulation des neutrophiles. De plus, les auteurs ont detecte de la MPO monomere dans le plasma de patients souffrant d'inflammation aigue. Leurs donnees suggerent que la decomposition de la MPO dimere en monomeres peut servir de mecanisme regulateur qui controle l'activation des neutrophiles dependante de la MPO et reduit les effets pro-inflammatoires de la MPO. [Traduit par la Redaction] Mots-cles : myeloperoxydase monomere, myeloperoxydase dimere, inflammation, neutrophiles, stress oxydant/halogenant., Introduction Myeloperoxidase (MPO; EC 1.11.2.2) is a heme-containing glycosylated oxidoreductase, which displays the halogenating activity catalyzing the 2-electron oxidation of halides ([Cl.sup.-], [Br.sup.-], and [I.sup.-]) and pseudohalide ([SCN.sup.-]) in the [...]

Mitogen-activated protein kinase (MAPK) signaling pathways are composed of a phosphorelay signaling module where an activated MAP kinase kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MAP2K) that in turn phosphorylates and activates a MAPK. The biological outcome of MAPK signaling is the regulation of cellular responses such as proliferation, differentiation, migration, and apoptosis. The MAP3K mixed lineage kinase 3 (MLK3) phosphorylates MAP2Ks to activate multiple MAPK signaling pathways, and MLK3 also has functions in cell signaling that are independent of its kinase activity. The recent elucidation of essential functions for MLK3 in tumour cell proliferation, migration, and invasion has drawn attention to the MLKs as potential therapeutic targets for cancer treatments. The mounting evidence that suggests a role for MLK3 in tumourigenesis and establishment of the malignant phenotype is the focus of this review. Key words: MLK3, MAPK, migration, tumourigenesis, proliferation, JNK, ERK. Les voies de signalisation des MAPK (mitogen-activated protein kinase) consistent en un module signaletique de type phospho-relai dans lequel une MAP kinase kinase kinase (MAP3K) phosphoryle et active une MAPK kinase (MAP2K) qui, a son tour, phosphoryle et active une MAPK. Le resultat biologique de la signalisation par MAPK est la regulation de reponses cellulaires telles la proliferation, la differenciation, la migration et l'apoptose. La MAP3K MLK3 (mixed lineage kinase 3) phosphoryle les MAP2K afin d'activer plusieurs voies de signalisation par MAPK, et la MLK3 exerce aussi des fonctions dans la signalisation cellulaire qui sont independantes de son activite kinase. L'elucidation recente des fonctions essentielles de la MLK3 dans la proliferation des cellules tumorales, leur migration et leur invasion a attire l'attention sur les MLK comme cibles therapeutiques potentielles pour le traitement du cancer. L'accumulation des donnees qui suggerent que la MLK3 joue un role dans la tumorigenese et l'etablissement d'un phenotype malin est l'objet du present article de synthese. [Traduit par la Redaction] Mots-cles: MLK3, MAPK, migration, tumorigenese, proliferation, JNK, ERK., Mitogen-activated protein kinase (MAPK) signaling The evolutionary conserved MAPK signaling pathways function to relay a wide range of extracellular signals from the cell surface to the nucleus, which results in [...]