PD37-03 EXPRESSION OF MUTANT
            PIK3CA
            IN MURINE UROTHELIAL CELLS PROVIDES A NOVEL MODEL OF EARLY STAGE BLADDER CANCER

Abstract Background Current non-invasive tests have limited sensitivities and lack capabilities of pre-operative risk stratification for bladder cancer (BC) diagnosis. We aimed to develop and validate a urine-based DNA methylation assay as a clinically feasible test for improving BC detection and enabling pre-operative risk stratifications. Methods A urine-based DNA methylation assay was developed and validated by retrospective single-center studies in patients of suspected BC in Cohort 1 (n = 192) and Cohort 2 (n = 98), respectively. In addition, a prospective single-center study in hematuria patient group (Cohort 3, n = 174) was used as a second validation of the model. Results The assay with a dual-marker detection model showed 88.1% and 91.2% sensitivities, 89.7% and 85.7% specificities in validation Cohort 2 (patients of suspected BC) and Cohort 3 (patients of hematuria), respectively. Furthermore, this assay showed improved sensitivities over cytology and FISH on detecting low-grade tumor (66.7–77.8% vs. 0.0–22.2%, 0.0–22.2%), Ta tumor (83.3% vs. 22.2–41.2%, 44.4–52.9%) and non-muscle invasive BC (NMIBC) (80.0–89.7% vs. 51.5–52.0%, 59.4–72.0%) in both cohorts. The assay also had higher accuracies (88.9–95.8%) in diagnosing cases with concurrent genitourinary disorders as compared to cytology (55.6–70.8%) and FISH (72.2–77.8%). Meanwhile, the assay with a five-marker stratification model identified high-risk NMIBC and muscle invasive BC with 90.5% sensitivity and 86.8% specificity in Cohort 2. Conclusions The urine-based DNA methylation assay represents a highly sensitive and specific approach for BC early-stage detection and risk stratification. It has a potential to be used as a routine test to improve diagnosis and prognosis of BC in clinic.

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Metallothionein-1 and -2 Expression in Cadmium- or Arsenic-Derived Human Malignant Urothelial Cells and Tumor Heterotransplants and as a Prognostic Indicator in Human Bladder Cancer

Toxicological Sciences ◽

10.1093/toxsci/kfj174 ◽

2006 ◽

Vol 91 (2) ◽

pp. 467-475 ◽

Cited By ~ 16

Author(s):

Xu Dong Zhou ◽

Donald A. Sens ◽

Mary Ann Sens ◽

Venugopal B. R. K. Namburi ◽

Rajendra K. Singh ◽

...

Keyword(s):

Bladder Cancer ◽

Prognostic Indicator ◽

Human Bladder Cancer ◽

Urothelial Cells ◽

Human Bladder

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Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

Chemical Research in Toxicology ◽

10.1021/tx500393y ◽

2015 ◽

Vol 28 (6) ◽

pp. 1144-1155 ◽

Cited By ~ 17

Author(s):

Julia E. Rager ◽

Sloane K. Tilley ◽

Samantha E. Tulenko ◽

Lisa Smeester ◽

Paul D. Ray ◽

...

Keyword(s):

Dna Methylation ◽

Bladder Cancer ◽

Urothelial Cells ◽

Novel Gene

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Extent of Risk-Aligned Surveillance for Cancer Recurrence Among Patients With Early-Stage Bladder Cancer

JAMA Network Open ◽

10.1001/jamanetworkopen.2018.3442 ◽

2018 ◽

Vol 1 (5) ◽

pp. e183442 ◽

Cited By ~ 5

Author(s):

Florian R. Schroeck ◽

Kristine E. Lynch ◽

Ji won Chang ◽

Todd A. MacKenzie ◽

John D. Seigne ◽

...

Keyword(s):

Bladder Cancer ◽

Early Stage ◽

Cancer Recurrence

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Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer

eLife ◽

10.7554/elife.43024 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

SungEun Kim ◽

Yubin Kim ◽

JungHo Kong ◽

Eunjee Kim ◽

Jae Hyeok Choi ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Molecular Mechanisms ◽

Molecular Subtype ◽

Early Stage ◽

Human Bladder Cancer ◽

Human Bladder ◽

Stromal Response

In bladder, loss of mammalian Sonic Hedgehog (Shh) accompanies progression to invasive urothelial carcinoma, but the molecular mechanisms underlying this cancer-initiating event are poorly defined. Here, we show that loss of Shh results from hypermethylation of the CpG shore of the Shh gene, and that inhibition of DNA methylation increases Shh expression to halt the initiation of murine urothelial carcinoma at the early stage of progression. In full-fledged tumors, pharmacologic augmentation of Hedgehog (Hh) pathway activity impedes tumor growth, and this cancer-restraining effect of Hh signaling is mediated by the stromal response to Shh signals, which stimulates subtype conversion of basal to luminal-like urothelial carcinoma. Our findings thus provide a basis to develop subtype-specific strategies for the management of human bladder cancer.

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Combination of Urine Exosomal mRNAs and lncRNAs as Novel Diagnostic Biomarkers for Bladder Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.667212 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haiming Huang ◽

Jialin Du ◽

Bo Jin ◽

Lu Pang ◽

Nan Duan ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Progression ◽

Rna Sequencing ◽

Molecular Mechanisms ◽

Early Stage ◽

Healthy Controls ◽

Direct Products ◽

Diagnostic Biomarkers ◽

Diagnostic Potential ◽

Urine Exosomes

BackgroundThe recent discovery of miRNAs and lncRNAs in urine exosomes has emerged as promising diagnostic biomarkers for bladder cancer (BCa). However, mRNAs as the direct products of transcription has not been well evaluated in exosomes as biomarkers for BCa diagnosis. The purpose of this study was to identify tumor progression-related mRNAs and lncRNAs in urine exosomes that could be used for detection of BCa.MethodsRNA-sequencing was performed to identify tumor progression-related biomarkers in three matched superficial tumor and deep infiltrating tumor regions of muscle-invasive bladder cancer (MIBC) specimens, differently expressed mRNAs and lncRNAs were validated in TCGA dataset (n = 391) in the discovery stage. Then candidate RNAs were chosen for evaluation in urine exosomes of a training cohort (10 BCa and 10 healthy controls) and a validation cohort (80 BCa and 80 healthy controls) using RT-qPCR. The diagnostic potential of the candidates were evaluated by receiver operating characteristic (ROC) curves.ResultsRNA sequencing revealed 8 mRNAs and 32 lncRNAs that were significantly upregulated in deep infiltrating tumor region. After validation in TCGA database, 10 markedly dysregulated RNAs were selected for further investigation in urine exosomes, of which five (mRNAs: KLHDC7B, CASP14, and PRSS1; lncRNAs: MIR205HG and GAS5) were verified to be significantly dysregulated. The combination of the five RNAs had the highest AUC to disguising the BCa (0.924, 95% CI, 0.875–0.974) or early stage BCa patients (0.910, 95% CI, 0.850 to 0.971) from HCs. The expression levels of these five RNAs were correlated with tumor stage, grade, and hematuria degrees.ConclusionsThese findings highlight the potential of urine exosomal mRNAs and lncRNAs profiling in the early diagnosis and provide new insights into the molecular mechanisms involved in BCa.

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Antioxidants and selenocompounds inhibit 3,5-dimethylaminophenol toxicity to human urothelial cells

Archives of Industrial Hygiene and Toxicology ◽

10.2478/aiht-2019-70-3159 ◽

2019 ◽

Vol 70 (1) ◽

pp. 18-29 ◽

Cited By ~ 4

Author(s):

Pinar Erkekoglu ◽

Ming-Wei Chao ◽

Chia-Yi Tseng ◽

Bevin P. Engelward ◽

Ozge Kose ◽

...

Keyword(s):

Oxidative Stress ◽

Bladder Cancer ◽

Antioxidant Enzyme ◽

Enzyme Activities ◽

Mammalian Cells ◽

Antioxidant Enzyme Activities ◽

Urothelial Cells ◽

Dna Breaks ◽

Primary Metabolite ◽

Stress Changes

AbstractExposure to alkyl anilines may lead to bladder cancer, which is the second most frequent cancer of the urogenital tract. 3,5-dimethylaniline is highly used in industry. Studies on its primary metabolite 3,5-dimethylaminophenol (3,5-DMAP) showed that this compound causes oxidative stress, changes antioxidant enzyme activities, and leads to death of different mammalian cells. However, there is no in vitro study to show the direct effects of 3,5-DMAP on human bladder and urothelial cells. Selenocompounds are suggested to decrease oxidative stress caused by some chemicals, and selenium supplementation was shown to reduce the risk of bladder cancer. The main aim of this study was to investigate whether selenocompounds organic selenomethionine (SM, 10 µmol/L) or inorganic sodium selenite (SS, 30 nmol/L) could reduce oxidative stress, DNA damage, and apoptosis in UROtsa cells exposed to 3,5-DMAP. 3,5-DMAP caused a dose-dependent increase in intracellular generation of reactive oxygen species, and its dose of 50 µmol/L caused lipid peroxidation, protein oxidation, and changes in antioxidant enzyme activities in different cellular fractions. The comet assay also showed single-strand DNA breaks induced by the 3,5-DMAP dose of 50 µmol/L, but no changes in double-strand DNA breaks. Apoptosis was also triggered. Both selenocompounds provided partial protection against the cellular toxicity of 3,5-DMAP. Low selenium status along with exposure to alkyl anilines can be a major factor in the development of bladder cancer. More mechanistic studies are needed to specify the role of selenium in bladder cancer.

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