title: Mitochondria and tumor progression in ulcerative colitis.
abstract: BACKGROUND
  The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis.
  
  
  METHODS
  Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C oxidase (COX), a component of the electron transport chain, and were quantified by multispectral imaging. For six additional progressors, nondysplastic and dysplastic biopsies were stained for COX and additional mitochondrial proteins including PGC1α, the master regulator of mitochondrial biogenesis. Mitochondrial DNA (mtDNA) copy number was determined by quantitative polymerase chain reaction. Generalized estimating equations with two-sided tests were used to account for correlation of measurements within individuals.
  
  
  RESULTS
  Nondysplastic biopsies of UC progressors showed statistically significant COX loss compared with UC nonprogressors by generalized estimating equation (-18.5 units, 95% confidence interval = -12.1 to -24.9; P < .001). COX intensity progressively decreased with proximity to dysplasia and was the lowest in adjacent to dysplasia and dysplastic epithelium. Surprisingly, COX intensity was statistically significantly increased in cancers. This bimodal pattern was observed for other mitochondrial proteins, including PGC1α, and was confirmed by mtDNA copy number.
  
  
  CONCLUSIONS
  Mitochondrial loss precedes the development of dysplasia, and it could be used to detect and potentially predict cancer. Cancer cells restore mitochondria, suggesting that mitochondria are needed for further proliferation. This bimodal pattern might be driven by transcriptional regulation of mitochondrial biogenesis by PGC1α.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Cigdem Himmetoglu
authors.initials: CH
authors.lastname: Ussakli
authors.forename: Anoosheh
authors.initials: A
authors.lastname: Ebaee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Binkley
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Rosa Ana
authors.initials: RA
authors.lastname: Risques
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D056915:DNA Copy Number Variations; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction / Q000379:methods; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D059506:Telomere Shortening; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D003576:Electron Transport Complex IV