title: Metabolic Pathway Signatures Associated with Urinary Metabolite Biomarkers Differentiate Bladder Cancer Patients from Healthy Controls.
abstract: OBJECTIVE
  Our previous high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA, based on our previously identified urinary metabolome.
  
  
  METHODS
  A total of 135 primary BCA samples and 26 control tissue samples from healthy volunteers were analyzed. The association between specific urinary metabolites and their related encoding genes was analyzed.
  
  
  RESULTS
  Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (CPT1A, CPT1B, CPT1C, CPT2, SLC25A20, and CRAT) or tryptophan metabolism (TPH1 and IDO1) was assessed by RT-PCR in our BCA cohort (n=135). CPT1B, CPT1C, SLC25A20, CRAT, TPH1, and IOD1 were significantly downregulated in tumor tissues compared to normal bladder tissues (p<0.05 all) of patients with non-muscle invasive BCA, whereas CPT1B, CPT1C, CRAT, and TPH1 were downregulated in those with muscle invasive BCA (p<0.05), with no changes in IDO1 expression.
  
  
  CONCLUSIONS
  Alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, which were the most perturbed pathways in BCA, were determined.
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.|Department of Urology, Graduate School of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Won Tae
authors.initials: WT
authors.lastname: Kim
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Seok Joong
authors.initials: SJ
authors.lastname: Yun
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Chunri
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Pildu
authors.initials: P
authors.lastname: Jeong
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Ye Hwan
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Il Seok
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors.forename: Ho Won
authors.initials: HW
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Sunghyouk
authors.initials: S
authors.lastname: Park
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Anseong, Korea.
authors.forename: Sung Kwon
authors.initials: SK
authors.lastname: Moon
authors.affiliation: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan, Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Urology, Graduate School of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Young Deuk
authors.initials: YD
authors.lastname: Choi
authors.affiliation: Section of Urological Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Isaac Yi
authors.initials: IY
authors.lastname: Kim
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, MA, USA. Jayoung.Kim@cshs.org.|Cancer Biology Division, Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea. wjkim@chungbuk.ac.kr.
authors.forename: Wun Jae
authors.initials: WJ
authors.lastname: Kim
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002331:Carnitine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; C116917:acylcarnitine; D002331:Carnitine
keywords: Bladder cancer; diagnostic marker; gene expression; qRT-PCR; urine metabolites