CD24 regulated gene expression and distribution of tight junction proteins is associated with altered barrier function in oral epithelial monolayers

<p>Abstract</p> <p>Background</p> <p>Control of intercellular penetration of microbial products is critical for the barrier function of oral epithelia. We demonstrated that CD24 is selectively and strongly expressed in the cells of the epithelial attachment to the tooth and the epithelial lining of the diseased periodontal pocket and studies <it>in vitro </it>showed that CD24 regulated expression of the epithelial intercellular adhesion protein E-cadherin.</p> <p>Results</p> <p>In the present study, the barrier function of oral epithelial cell monolayers to low molecular weight dextran was assayed as a model for the normal physiological function of the epithelial attachment to limit ingress of microbial products from oral microbial biofilms. Paracellular transfer of low molecular weight dextran across monolayers of oral epithelial cells was specifically decreased following incubation with anti-CD24 peptide antibody whereas passage of dextran across the monolayer was increased following silencing of mRNA for CD24. Changes in barrier function were related to the selective regulation of the genes encoding zonula occludens-1, zonula occludens-2 and occludin, proteins implicated in tight junctions. More particularly, enhanced barrier function was related to relocation of these proteins to the cell periphery, compatible with tight junctions.</p> <p>Conclusion</p> <p>CD24 has the constitutive function of maintaining expression of selected genes encoding tight junction components associated with a marginal barrier function of epithelial monolayers. Activation by binding of an external ligand to CD24 enhances this expression but is also effective in re-deployment of tight junction proteins that is aligned with enhanced intercellular barrier function. These results establish the potential of CD24 to act as a potent regulator of the intercellular barrier function of epithelia in response to local microbial ecology.</p

Expression of RFC/SLC19A1 is Associated with Tumor Type in Bladder Cancer Patients

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer. In Egypt, the pattern of bladder cancer is unique in that both the transitional and squamous cell types prevail. Despite much research on the topic, it is still difficult to predict tumor progression, optimal therapy and clinical outcome. The reduced folate carrier (RFC/SLC19A1) is the major transport system for folates in mammalian cells and tissues. RFC is also the primary means of cellular uptake for antifolate cancer chemotherapeutic drugs, however, membrane transport of antifolates by RFC is considered as limiting to antitumor activity. The purpose of this study was to compare the mRNA expression level of RFC/SLC19A1 in urothelial and non-urothelial variants of bladder carcinomas. Quantification of RFC mRNA in the mucosa of 41 untreated bladder cancer patients was performed using RT-qPCR. RFC mRNA steady-state levels were ∼9-fold higher (N = 39; P<0.0001) in bladder tumor specimens relative to normal bladder mRNA. RFC upregulation was strongly correlated with tumor type (urothelial vs. non-urothelial; p<0.05) where median RFC mRNA expression was significantly (p<0.05) higher in the urothelial (∼14-fold) compared to the non-urothelial (∼4-fold) variant. This may account for the variation in response to antifolate-containing regimens used in the treatment of either type. RFC mRNA levels were not associated with tumor grade (I, II and III) or stage (muscle-invasive vs. non-muscle invasive) implying that RFC cannot be used for prognostic purposes in bladder carcinomas and its increased expression is an early event in human bladder tumors pathogenesis. Further, RFC can be considered as a potential marker for predicting response to antifolate chemotherapy in urothelial carcinomas

Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors

<p>Abstract</p> <p>Background</p> <p>We conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers.</p> <p>Methods</p> <p>445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk.</p> <p>Results</p> <p>Any previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk.</p> <p>Conclusions</p> <p>Occupational exposures and family history of cancer with young onset were important risk factors among never smokers.</p

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk

Experience of, awareness of and help-seeking for potential cancer symptoms in smokers and non-smokers: A cross-sectional study

Background Presenting to primary care with potential cancer symptoms is contingent on one’s ability to recognize potentially serious symptoms. We investigated differences between smokers and non-smokers in symptoms experienced, awareness and consulting of potential respiratory, head and neck cancer symptoms. Methods Smokers and non-smokers aged over 50 from Yorkshire general practice lists were sent a postal questionnaire asking about symptoms, consulting and awareness of cancer symptoms. Data were analysed using STATA14. Results Response rate after one reminder was 30.5% (1205/3954). Smoking status was associated with experience of cough (p<0.001), breathlessness (p = 0.002) and tiredness (p = 0.004) with smokers (25.8% of population) more likely than never-smokers (53.6% of population) to experience all three symptoms (cough OR = 2.56;95%CI[1.75–3.75], breathlessness OR = 2.39;95%CI[1.43–4.00], tiredness OR = 1.57;95%CI[1.12–2.19]). Smoking status was associated with awareness of breathlessness as a potential cancer symptom (p = 0.035) and consulting for cough (p = 0.011) with smokers less likely to consult than never-smokers (OR = 0.37;95% CI[0.17–0.80]). Conclusion Our findings suggest that current smokers are more likely to experience cough, breathlessness and tiredness, but are less likely to consult for cough than never-smokers. To increase cancer awareness and promote consulting among smokers, innovative interventions improving symptom recognition and empowering smokers to seek help are required

Menopausal Status Modifies Breast Cancer Risk Associated with the Myeloperoxidase (MPO) G463A Polymorphism in Caucasian Women: A Meta-Analysis

BACKGROUND: Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase (MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls. METHODOLOGY/PRINCIPAL FINDINGS: To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta-analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity AA genotype of MPO in the pre-menopausal population showed significantly reduced risk (OR 0.56-0.57, p = 0.03) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR 1.14; p = 0.34-0.36). High intake of antioxidants (OR 0.67-0.86, p = 0.04-0.05) and carotenoids (OR 0.68-0.86, p = 0.03-0.05) conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high (OR 0.42-0.69, p = 0.04). In post-menopausal women, effect of low intake elicited susceptibility (OR 1.19-1.67, p = 0.07-0.17) to breast cancer. CONCLUSIONS/SIGNIFICANCE: Based on a homogeneous Caucasian population, the MPO G463A polymorphism places post-menopausal women at risk for breast cancer, where this effect is modified by diet

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta&lt;5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta&lt;5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites

Spontaneous and radiation-induced chromosomal instability and persistence of chromosome aberrations after radiotherapy in lymphocytes from prostate cancer patients

The aim of the study was to compare the spontaneous and ex vivo radiation-induced chromosomal damage in lymphocytes of untreated prostate cancer patients and age-matched healthy donors, and to evaluate the chromosomal damage, induced by radiotherapy, and its persistence. Blood samples from 102 prostate cancer patients were obtained before radiotherapy to investigate the excess acentric fragments and dicentric chromosomes. In addition, in a subgroup of ten patients, simple exchanges in chromosomes 2 and 4 were evaluated by fluorescent in situ hybridization (FISH), before the onset of therapy, in the middle and at the end of therapy, and 1 year later. Data were compared to blood samples from ten age-matched healthy donors. We found that spontaneous yields of acentric chromosome fragments and simple exchanges were significantly increased in lymphocytes of patients before onset of therapy, indicating chromosomal instability in these patients. Ex vivo radiation-induced aberrations were not significantly increased, indicating proficient repair of radiation-induced DNA double-strand breaks in lymphocytes of these patients. As expected, the yields of dicentric and acentric chromosomes, and the partial yields of simple exchanges, were increased after the onset of therapy. Surprisingly, yields after 1 year were comparable to those directly after radiotherapy, indicating persistence of chromosomal instability over this time. Our results indicate that prostate cancer patients are characterized by increased spontaneous chromosomal instability. This instability seems to result from defects other than a deficient repair of radiation-induced DNA double-strand breaks. Radiotherapy-induced chromosomal damage persists 1 year after treatment

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13-1.27; p = 5.6 x 10(-10)) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19-1.35; p = 1.0 x 10(-12)). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers