Role of coxsackie- and adenovirus receptor (CXADR/CAR) in the regulation of cell plasticity in cancer and inflammation

The coxsackie- and adenovirus receptor (CXADR) is a transmembrane protein, which localizes at tight junctions (TJ) in epithelial cells. As highlighted by its name, CXADR was initially identified as a receptor for type C adenoviruses and group B coxsackieviruses. Subsequently, CXADR has been shown to mediate cell-cell adhesion, immune cell activation and cellular signaling. Unlike other TJ components, CXADR is vital for the early stages of development. Deregulation of CXADR is frequently observed in pathological conditions including cancer and chronic inflammation. However, mechanistic insight into the role of CXADR in pathophysiology has been lacking. The overall aim of this thesis was therefore to study the role of CXADR in cancer progression and inflammatory diseases. In Paper I, we show that CXADR regulates the capacity of breast cancer cells to undergo epithelial-mesenchymal transition (EMT) in response to the cytokine TGF-β1. The mechanism was traced to a previously unidentified role of CXADR in acting as a negative regulator of the AKT signaling pathway by forming a signalosome with, PTEN and PHLPP2. Through lossand gain-of-function experiments we showed that by regulating the stability of the signalosome at tight junction, CXADR controls AKT activity and epithelial-mesenchymal plasticity in breast cancer cells. Moreover, we found that loss of CXADR correlated with loss of PTEN and PHLPP2, and poor prognosis in luminal A breast cancer. In Paper II, we found that CXADR expression is significantly induced during the formation of atherosclerotic plaques in arterial walls. Macrophages were identified as a previously unknown cellular source of CXADR in both murine and human atherosclerotic plaques. A combination of gene expression profiling, mass spectrometric analysis and in vitro studies using human monocytes (THP1 cells), revealed that the induction of CXADR expression is linked to monocyte-macrophage differentiation and further polarization into M1 subtype, and foam cells. Intriguingly, we also found a significant correlation between CXADR and receptors for other viruses, associated with atherosclerosis in human plaques. In Paper III, inspired by the results from Paper I, we show that CXADR also regulates the metabolic arm downstream of AKT. We found that CXADR controls glucose uptake in various types of cells by regulating the expression and localization of the glucose transporter GLUT-1. Further studies revealed that CXADR expression is upregulated in heart and liver tissues in a mouse model of type 2 diabetes (T2D). In line with this, we found that CXADR expression is induced by IL-6, an inflammatory cytokine which is known to play a role in T2D. In conclusion, the results presented in this thesis provide a novel and mechanistic insight into the role of CXADR as a pathogenic factor in breast cancer progression and suggest that CXADR contributes to the progression of chronic inflammatory diseases including atherosclerosis and T2D. This may offer new possibilities for using CXADR as a target to develop novel diagnostic tools and therapeutic strategies in cancer and inflammation

Different Regulation of Glut1 Expression and Glucose Uptake during the Induction and Chronic Stages of TGFβ1-Induced EMT in Breast Cancer Cells

Transforming growth factor beta 1 (TGF-β1) is associated with epithelial-mesenchymal transition (EMT), lymph metastasis, and poor prognosis in breast cancer. Paradoxically, TGF-β1 is also a potent inhibitor of cell proliferation. TGF-β1-induced EMT involves activation of several pathways including AKT, which also regulates glucose uptake. Recent data show that prolonged TGF-β1 exposure leads to a more stable EMT phenotype in breast cancer cells. However, whether this is linked to changes in glucose metabolism is not clear. Here, we used a model of TGF-β1-induced EMT in mammary epithelial cells to study the regulation of Glut1 and EMT markers during the induction compared to a prolonged phase of EMT by western blot, immunofluorescence and qPCR analysis. We also measured cell proliferation and uptake of the glucose analogue 2-NDBG. We found that EMT induction was associated with decreased Glut1 expression and glucose uptake. These effects were linked to reduced cell proliferation rather than EMT. Knockdown of Glut1 resulted in growth inhibition and less induction of vimentin during TGF-β1-induced EMT. Intriguingly, Glut1 levels, glucose uptake and cell proliferation were restored during prolonged EMT. The results link Glut1 repression to the anti-proliferative response of TGF-β1 and indicate that re-expression of Glut1 during chronic TGF-β1 exposure allows breast cancer cells to develop stable EMT and proliferate, in parallel

Oral health and quality of life in children: A cross-sectional study

Introduction: The relationship of oral health (OH) with the quality of life (QL) is multidimensional; the extent to which oral disorders disrupt an individual′s normal function may affect health-related QL, particularly among children. The current study aimed to examine the relationship between clinical OH variables, psychological, social, and demographic factors with regard to OH-related QL (OHRQL) in the children of Isfahan province, Iran. Materials and Methods: Data relevant to the characteristics, psychological, dental, and demographic factors of 336 children aged 11-15 were assessed. These characteristics included sociodemographic data, sense of coherence (SOC), self-esteem, and children′s health locus of control (HLC). The clinical variables that were implicated to be effective on the QL were assessed via an oral examination. The parameters assessed included caries, periodontal disease, malocclusion, and traumatic dental injuries. Finally, the data was analyzed using Statistical Package for the Social Sciences (SPSS) software and P-value was set at 0.05. Results: The results indicate that oral disease, the extent of treatment-need, self-reported symptoms, and degree of dysfunction were influential in QL. Bivariate (Spearman and Pearson) analysis showed that there was a relationship between decayed, missing, and filled teeth (DMFT) and QL score (r = 0.4, P-value = 0.03) and gender and total self-esteem (r = 0.8, P-value = 0.009). Self-esteem and index of orthodontic treatment need (IOTN) (P-value = 0.01), education level of the parents (P-value = 0.03), and overall health (P-value = 0.001) significantly influenced OHRQL. Conclusions: The findings of our study indicate that oral disease, the extent of treatment-need, self-reported symptoms, and degree of dysfunction were influential in the QL

Induction of the Coxsackievirus and Adenovirus Receptor in Macrophages During the Formation of Atherosclerotic Plaques.

Multiple viruses are implicated in atherosclerosis, but the mechanisms by which they infect cells and contribute to plaque formation in arterial walls are not well understood. Based on reports showing the presence of enterovirus in atherosclerotic plaques we hypothesized that the coxsackievirus and adenovirus receptor (CXADR/CAR), although absent in normal arteries, could be induced during plaque formation. Large-scale microarray and mass spectrometric analyses revealed significant up-regulation of CXADR messenger RNA and protein levels in plaque-invested carotid arteries compared with control arteries. Macrophages were identified as a previously unknown cellular source of CXADR in human plaques and plaques from Ldr-/-Apob100/100 mice. CXADR was specifically associated with M1-polarized macrophages and foam cells and was experimentally induced during macrophage differentiation. Furthermore, it was significantly correlated with receptors for other viruses linked to atherosclerosis. The results show that CXADR is induced in macrophages during plaque formation, suggesting a mechanism by which enterovirus infect cells in atherosclerotic plaques.info:eu-repo/semantics/publishe