title: Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression.
abstract: Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.
authors: Department of Molecular and Cell Biology, Verna and Marrs McLean Department of Biochemistry and Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Nagireddy
authors: N
authors: Putluri
authors: Ali
authors: A
authors: Shojaie
authors: Vihas T
authors: VT
authors: Vasu
authors: Shaiju K
authors: SK
authors: Vareed
authors: Srilatha
authors: S
authors: Nalluri
authors: Vasanta
authors: V
authors: Putluri
authors: Gagan Singh
authors: GS
authors: Thangjam
authors: Katrin
authors: K
authors: Panzitt
authors: Christopher T
authors: CT
authors: Tallman
authors: Charles
authors: C
authors: Butler
authors: Theodore R
authors: TR
authors: Sana
authors: Steven M
authors: SM
authors: Fischer
authors: Gabriel
authors: G
authors: Sica
authors: Daniel J
authors: DJ
authors: Brat
authors: Huidong
authors: H
authors: Shi
authors: Ganesh S
authors: GS
authors: Palapattu
authors: Yair
authors: Y
authors: Lotan
authors: Alon Z
authors: AZ
authors: Weizer
authors: Martha K
authors: MK
authors: Terris
authors: Shahrokh F
authors: SF
authors: Shariat
authors: George
authors: G
authors: Michailidis
authors: Arun
authors: A
authors: Sreekumar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000652:urine*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000652:urine*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1