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A disintegrin-like and metalloprotease with therombospondin type1 motif 8 (ADAMTS8) plays an important role in many malignancies. However, the clinical and biological significance of ADAMTS8 in breast cancer remain unknown. In this study, the clinical data from 1066 breast cancer patients were analyzed by The Cancer Genome Atlas (TCGA) database, and were analyzed using the correlation between ADAMTS8 expression and the clinicopathological features and prognoses. The CCK-8 assay, clone formation assay, flow cytometry and Transwell assay were used to characterize the effects of ADAMTS8 on proliferation, migration and invasion of breast cancer cells. Gene set enrichment analysis (GSEA) and western blotting were used to identify the potential molecular mechanism on how ADAMTS8 exert its biological function. ADAMTS8 overexpression correlated longer overall survival (OS) and progression-free survival (PFS). ADAMTS8 was considered as an independent prognostic factor for OS. ADAMTS8 overexpression inhibited breast cancer cell proliferation, migration and invasion in vitro, and induced G2/M cell cycle arrest. ADAMTS8 was also involved in cell cycle regulation and was associated with the EGFR/Akt signaling pathway. ADAMTS8 knockdown showed the reverse effect. Together, the results showed that ADAMTS8 functioned as a tumor suppressor gene (TGS) and could be a prognostic biomarker for breast cancer. [ABSTRACT FROM AUTHOR]

Oxygen transport behavior in erythrocyte suspension or in hemoglobin solution was studied as a potential therapeutic model for the clinical treatment of blood loss, and this can also provide physiological data with which to evaluate blood substitutes. In the present project, we examined the in vitro kinetics of hemoglobin binding to and releasing oxygen, to provide detailed oxygen-flux measurements for unmodified hemoglobin solutions and erythrocyte suspensions in human, as well as other vertebrates. An in vitro method was used, based on a widely used artificial system, with the oxygen saturation level being detected in real time. Results from this study indicated that the kinetic curves of human erythrocyte suspensions and hemoglobin solutions were either S-shaped or hyperbolic, respectively. Based on these curves, the significance of [T.sub.50] emerged in our investigation, where [T.sub.50] is defined as the time needed for 50% hemoglobin to be saturated with oxygen, and reflects the efficiency with which hemoglobin carries oxygen. This parameter may be used to diagnose blood diseases, and could be a standard for evaluating blood substitutes. In this study, we also compared the [T.sub.50] of 4 species of vertebrates, and found that it shows a distinct efficiency of oxygen binding related to species, and potentially reveals the evolutionary function of hemoglobin and its possible adaptation to the environment. Key words: oxygen transport, kinetic curve, erythrocyte, hemoglobin, [T.sub.50]. Le transport d'oxygene chez les erythrocytes ou dans une solution d'hemoglobine a ete etudie en tant que modele therapeutique potentiel pour traiter cliniquement la perte sanguine et pour fournir aussi des donnees physiologiques permettant d'en evaluer la valeur comme substituts sanguins. Dans le present projet, nous avons examine les cinetiques de liaison et de liberation d'oxygene par l'hemoglobine in vitro afin d'obtenir des mesures detaillees du flux d'oxygene dans des solutions d'hemoglobine non modifiee et des suspensions d'erythrocytes chez l'humain ainsi que chez d'autres vertebres. Une methode in vitro basee sur un systeme artificiel largement employe a ete utilisee et le niveau de saturation en oxygene a ete detecte en temps reel. Les resultats de cette etude ont indique que les courbes cinetiques des suspensions d'erythrocytes et des solutions d'hemoglobine d'origine humaine etaient respectivement en forme de S et hyperbolique. Selon ces courbes, l'importance du [T.sub.50] est ressortie de nos travaux. Le [T.sub.50] est defini comme le temps requis pour atteindre 50 % de saturation en oxygene et reflete l'efficacite de transport d'oxygene de l'hemoglobine, ce qui peut contribuer au diagnostic des maladies sanguines et constituer un standard des substituts sanguins. Dans cette etude, nous avons aussi compare les [T.sub.50] de 4 especes de vertebres, lesquels montrent des efficacites de liaison d'oxygene distinctes et revelent potentiellement la fonction evolutive de l'hemoglobine et son adaptation possible a l'environnement. Mots-cles : transport d'oxygene, courbe cinetique, erythrocytes, hemoglobine, [T.sub.50]. [Traduit par la Redaction], Introduction The hemoglobin oxygen dissociation curve (HODC), including [P.sub.50] (the partial pressure of [O.sub.2], where 50% of the hemoglobin is saturated) is widely used as a criterion for assessing the [...]

Aim: Zinc finger and BTB domain‐containing protein 28 (ZBTB28) is a potential tumor suppressor for some cancers. However, its epigenetic regulation and functions in renal cell carcinoma (RCC) remain to be elucidated. Methods: The expression of ZBTB28 mRNA was analyzed by semi‐quantitative reverse transcription polymerase chain reaction (PCR) in nine RCC cell lines and normal kidney tissues. Methylation status of ZBTB28 promoter was assessed by methylation‐specific PCR in RCC cell lines, primary RCC, tumors and adjacent tissues. The involvement of ZBTB28 in cell proliferation and migration was investigated. Results: ZBTB28 promoter was hypermethylated in 88.9% (8/9) of RCC cell lines with reduced ZBTB28 mRNA expression, and could be reversed by DNA methyltransferase inhibitors. The methylation of ZBTB28 promoter was detected in 73.5% (36/49) of primary RCC tissues, compared with 7.1% (1/14) in normal tissues. Overexpression of ZBTB28 significantly inhibited RCC cell proliferation and migration, and induced apoptosis. Further analyses revealed that ZBTB28 upregulation could inhibit multiple oncogenic signaling transduction pathways. Conclusion: ZBTB28 is frequently silenced by promoter methylation in RCC pathogenesis and functions as a novel tumor suppressive gene. ZBTB28 may be a potential target for the development of RCC therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lung cancer is the most frequently diagnosed cancer worldwide. Epigenetic regulation contributes to lung cancer pathogenesis. The ADAMTS18 tumor suppressor gene is inactivated in some cancers, but its involvement in lung cancer has not been shown. Immunohistochemistry, quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR), and methylation‐specific PCR were used to assay ADAMTS18 expression and promoter methylation in lung tumor tissues and adjacent tissues. Cell viability, transwell, and wound‐healing assays, as well as flow cytometry were used to characterize the biological activity of ADAMTS18. The influence of ADAMTS18 on protein expression was assayed using western blots analysis, and its effect on chemosensitivity was assayed by the response to cisplatin. We found that ADAMTS18 was silenced in lung cancer cells by promoter methylation. Demethylation by the DNA methyltransferase inhibitor 5‐aza‐2′‐deoxycytidine, with or without the histone deacetylase inhibitor trichostatin A, restored ADAMTS18 expression. Compared with normal lung tissue, ADAMTS18 in lung tumors was frequently methylated. Overexpression of ADAMTS18 in lung cancer cells inhibited cell proliferation, migration, and invasiveness and induced G0/G1 cell cycle arrest. Furthermore, ADAMTS18 suppressed epidermal growth factor receptor/protein kinase B (EGFR/AKT) signaling, which sensitized lung cancer cells to cisplatin. Thus, our results demonstrated that the tumor suppressor gene ADAMTS18 was downregulated in lung cancer by promoter CpG methylation, and it promoted sensitivity to cisplatin via EGFR/AKT signaling. Our study suggests that ADAMTS18 promoter methylation is a potential epigenetic biomarker for early detection of lung cancer and warrants investigation as a therapeutic target for early‐stage lung cancer. Our results demonstrated that the tumor suppressor gene ADAMTS18 was downregulated in lung cancer by promoter CpG methylation, and it promoted sensitivity to cisplatin via epidermal growth factor receptor/protein kinase B signaling. Our study suggests that ADAMTS18 promoter methylation is a potential epigenetic biomarker for early detection of lung cancer and warrants investigation as therapeutic target for early‐stage lung cancer. [ABSTRACT FROM AUTHOR]

Recent studies suggest that paired box 5 (PAX5) is down-regulated in multiple tumours through its promoter methylation. However, the role of PAX5 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear. The aim of this study is to examine PAX5 expression, its methylation status, biological functions and related molecular mechanism in NSCLC. We found that PAX5 was widely expressed in normal adult tissues but silenced or down-regulated in 88% (7/8) of NSCLC cell lines. PAX5 expression level was significantly lower in NSCLC than that in adjacent non-cancerous tissues (P = 0.0201). PAX5 down-regulation was closely associated with its promoter hypermethylation status and PAX5 expression could be restored by demethylation treatment. Frequent PAX5 promoter methylation in primary tumours (70%) was correlated with lung tumour histological types (P = 0.006). Ectopic expression of PAX5 in silenced lung cancer cell lines (A549 and H1975) inhibited their colony formation and cell viability, arrested cell cycle at G2 phase and suppressed cell migration/invasion as well as tumorigenicity in nude mice. Restoration of PAX5 expression resulted in the down-regulation of β-catenin and up-regulation of tissue inhibitors of metalloproteinase 2, GADD45G in lung tumour cells. In summary, PAX5 was found to be an epigenetically inactivated tumour suppressor that inhibits NSCLC cell proliferation and metastasis, through down-regulating the b-catenin pathway and up-regulating GADD45G expression. [ABSTRACT FROM AUTHOR]

Abstract: The RGD motif on the extracellular matrix or cell surface, together with its integrin receptors, constitutes a major recognition system for cell adhesion. There are several erythrocyte major membrane skeletal proteins, e.g., α spectrin, ankyrin, and protein 4.2, that bear an RGD motif. However, it is not known whether the RGD/integrin recognition system is utilized in the erythrocyte-macrophage adhesion during erythrophagocytosis. Here we report that the RGD motif of ankyrin, but not others, is recognized by the αvβ3 integrin receptor. In addition, the RGD motif of ankyrin, a peripheral membrane protein, can be externalized onto the cell surface when erythrocytes are incubated with calcium and sheared both at physiological levels. Furthermore, the erythrocyte-macrophage adhesion can be specifically inhibited by ankyrin and/or αvβ3. Thus, externalization of ankyrin followed by RGD/integrin recognition may be a novel mechanism by which erythrocytes adhere to macrophages preceding phagocytosis. [Copyright &y& Elsevier]