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Association between Arsenic Level, Gene Expression in Asian Population, and In Vitro Carcinogenic Bladder Tumor.

ABSTRACT: The IARC classified arsenic (As) as "carcinogenic to humans." Despite the health consequences of arsenic exposure, there is no molecular signature available yet that can predict when exposure may lead to the development of disease. To understand the molecular processes underlying arsenic exposure and the risk of disease development, this study investigated the functional relationship between high arsenic exposure and disease risk using gene expression derived from human exposure. In this study, a three step analysis was employed: (1) the gene expression profiles obtained from two diverse arsenic-exposed Asian populations were utilized to identify differentially expressed genes associated with arsenic exposure in human subjects, (2) the gene expression profiles induced by arsenic exposure in four different myeloma cancer cell lines were used to define common genes and pathways altered by arsenic exposure, and (3) the genetic profiles of two publicly available human bladder cancer studies were used to test the significance of the common association of genes, identified in step 1 and step 2, to develop and validate a predictive model of primary bladder cancer risk associated with arsenic exposure. Our analysis shows that arsenic exposure to humans is mainly associated with organismal injury and abnormalities, immunological disease, inflammatory disease, gastrointestinal disease, and increased rates of a wide variety of cancers. In addition, arsenic exerts its toxicity by generating reactive oxygen species (ROS) and increasing ROS production causing the imbalance that leads to cell and tissue damage (oxidative stress). Oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell specifically; there is significant evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Therefore, we examined the relation of differentially expressed genes due to exposure of arsenic in human and bladder cancer and developed a bladder cancer risk prediction model. In this study, integrin-linked kinase (ILK) was one of the most significant pathways identified between both arsenic exposed population which plays a key role in eliciting a protective response to oxidative damage in epidermal cells. On the other hand, several studies showed that arsenic trioxide (ATO) is useful for anticancer therapy although the mechanisms underlying its paradoxical effects are still not well understood. ATO has shown remarkable efficacy for the treatment of multiple myeloma; therefore, it will be helpful to understand the underlying cancer biology by which ATO exerts its inhibitory effect on the myeloma cells. Our study found that MAPK is one of the most active network between arsenic gene and ATO cell line which is involved in indicative of oxidative/nitrosative damage and well associated with the development of bladder cancer. The study identified a unique set of 147 genes associated with arsenic exposure and linked to molecular mechanisms of cancer. The risk prediction model shows the highest prediction ability for recurrent bladder tumors based on a very small subset (NKIRAS2, AKTIP, and HLA-DQA1) of the 147 genes resulting in AUC of 0.94 (95% CI: 0.744-0.995) and 0.75 (95% CI: 0.343-0.933) on training and validation data, respectively.

SUBMITTER: Singhal S

PROVIDER: S-EPMC8760535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Arsenic is one of the greatest hazards as an environmental carcinogen. At the same time it is also a promising anticancer agent, that can be used to treat acute promyelocytic leukemia (APL) and some other tumors. Arsenic trioxide (ATO) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells. However, the molecular mechanisms that govern these paradoxical effects of arsenic in bladder cancer remain unclear. We speculate that they share the common mechanism that arsenic binds to the target proteins and subsequently impacts the expression of downstream genes. To address this issue, three Gene Set Enrichments (GSE) were loaded from the Gene Expression Omnibus (GEO) database with four expression matrices. Three of them were mice samples at exposure times of 1, 2, and 12 weeks, and the last was a human urothelial cell (HUC1) sample. Differentially expressed genes (DEGs) from 4 expression groups were identified at iDEP and analyzed at Metascape and Cytoscape for signaling pathway analysis and protein-protein interaction (PPI) analysis. The web-portals UALCAN and GEPIA were used to analyze the role of DEGs in the crosstalk between carcinogenic and anticancer effects. The putative downstream genes of arsenic binding proteins were retrieved using the Cistrome Data Browser. Real-time PCR was used to validate the expression of DEGs. The signaling pathways referred to lipid metabolism. Responses to various stimuli or hormones were overrepresented in 4 expression matrices. The PPI network emphasized the role of KRAS and TNF signaling in different groups. Furthermore, BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10 played an important role in the crosstalk between carcinogenic and anticancer effects in bladder cancer. Arsenic may impact the activity of ACTB, BACH1, NME2, RBBP4, PARP1, and PML by direct binding, and thus influence the expression of downstream genes such as PAX6, MLLT11, LTBP1, PCSK5, ZFP36, COL8A2, and IL1R2. Arsenic exerted carcinogenic and anticancer functions by altering the expression of crosstalk genes such as BDKRB2, FOS, NR4A1, PLAU, SH3BGRL, and F10, and these were due to arsenic binding proteins.

Project description:ImportanceWith the rapidly aging population, the burden of visual impairment (VI) and cognitive decline is expected to increase. Previous cross-sectional studies suggest an association between these 2 health outcomes. However, few longitudinal reports have examined this association, and to our knowledge, no studies have been performed in Asian populations. Further investigation on this association may help to better identify individuals at risk of cognitive decline.ObjectiveTo examine the longitudinal association between VI and decline in cognitive function in a multiethnic Asian population.Design, setting, and participantsIn this longitudinal, population-based, prospective cohort study, Chinese, Indian, and Malay adults 60 years or older at baseline were recruited from the Singapore Epidemiology of Eye Diseases (SEED) study. At baseline, participants from the SEED study were recruited under 3 studies: the Singapore Malay Eye Study (SiMES; 2004-2006), the Singapore Indian Eye Study (SINDI; 2007-2009), and the Singapore Chinese Eye Study (SCES; 2009-2011). Eligible participants were reexamined after 6 years (2011-2013 for SiMES, 2013-2015 for SINDI, and 2015-2017 for SCES). Data analysis was performed from November 1 to 24, 2019.ExposuresVisual impariment was defined as presenting visual acuity worse than 20/40 based on the better-seeing eye.Main outcomes and measuresCognitive function was assessed using a locally validated Abbreviated Mental Test (AMT). The association between baseline VI and change in AMT score was determined using the multivariable linear regression model adjusting for baseline age; sex; race/ethnicity; presence of diabetes, hyperlipidemia, hypertension, and chronic kidney disease; history of cardiovascular disease; smoking status; alcohol intake; body mass index; educational status; and AMT score.ResultsA total of 2478 individuals (1256 [50.7%] male; 1073 Chinese, 768 Indian, and 637 Malay adults) with mean (SD) age of 67.6 (5.6) years were evaluated, of whom 489 (19.7%) had reduction in AMT scores over 6 years. Baseline VI was associated with a decrease in AMT score over 6 years (β = -0.27; 95% CI, -0.37 to -0.17; P < .001). When change in vision over 6 years was evaluated, unchanged or deteriorated VI was associated with a decrease in AMT score over 6 years (β = -0.29; 95% CI, -0.40 to -0.18; P < .001). Among individuals with baseline VI and a substantial decrease in AMT score of 3 units or more over 6 years, the leading causes of VI were undercorrected refractive error (14 [45.2%]) and cataract (11 [35.5%]).Conclusions and relevanceIn this study, poor vision was independently associated with a decline in cognitive function. Causes of visual loss in these cases were mostly preventable, further suggesting that preserving good vision may be an important interventional strategy for mitigating cognitive decline.

Project description:ObjectivesTo compare the risk of bladder cancer and bladder cancer mortality among patients with chronic bladder catheterisation (indwelling or intermittent) to patients from the general population.DesignRetrospective cohort study.SettingPopulation-based study in Ontario, Canada between 2003 and 2018.ParticipantsAdult patients 18-90 years of age with chronic bladder catheterisation were hard matched to patients from the general population without a history of bladder catheterisation.InterventionsThe presence of a chronic catheter was defined as a minimum of two physician encounters for bladder catheterisation, suprapubic tube insertion or home care for catheter care separated by at least 28 days. Urinary tract infection (UTI) rates were collected.Main outcome measuresBladder cancer and bladder cancer-specific mortality after a 1-year lag period were compared between groups.ResultsWe identified 36 903 patients with chronic catheterisation matched to 110 709 patients without a history of catheterisation. Patients were followed for a median of 8.8 years (IQR: 5.2-11.9 years). The median age was 62 years (IQR: 50-71) and 52% were female. More patients in the catheter group developed bladder cancer (393 (1.1%) vs 304 (0.3%),p<0.001). There were 106 (0.3%) bladder cancer deaths in the catheter group and 59 (0.1%) in the comparison group (p<0.001). Chronic catheterisation (adjusted subdistribution HR (sdHR)=4.80, 95% CI: 4.26 to 5.42,p<0.001) and the number of UTIs (adjusted sdHR=1.04 per UTI, 95% CI: 1.04 to 1.05,p<0.001) were independent predictors of bladder cancer. The relative rate of bladder cancer-specific death was more than eightfold higher among patients with chronic catheterisation (adjusted sdHR=8.68, 95% CI: 6.97 to 10.81,p<0.001). Subgroup analysis among patients with neurogenic bladder and bladder calculi similarly revealed an increased risk of bladder cancer diagnosis and mortality. Bladder cancer risk was highest among patients in the two longest catheter duration quintiles (2.9-5.9 and 5.9-15.5 years).ConclusionsThis is the first study to quantify the increase in bladder cancer incidence and mortality in a large, diverse cohort of patients with chronic indwelling or intermittent bladder catheterisation. The risk was highest among patients with a chronic catheter beyond 2.9 years.

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Association between Arsenic Level, Gene Expression in Asian Population, and In Vitro Carcinogenic Bladder Tumor.

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