title: Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice.
abstract: OBJECTIVE
  Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC.
  
  
  METHODS
  Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8(-/-)) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors.
  
  
  RESULTS
  AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8(-/-) mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8(-/-) mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8(-/-) mice than in wild-type mice. Palpable masses were seen in the AKR1B8(-/-) mice only, not in wild-type.
  
  
  CONCLUSIONS
  AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Ruilan
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Wancai
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: John
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Chenfei
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Bu
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Laxiang
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zu
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology at Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Mei Chris
authors.initials: MC
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
authors.affiliation: Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China. dcao@siumed.edu dfliao66@aliyun.com.
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois. Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China. dcao@siumed.edu dfliao66@aliyun.com.
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
mesh_terms: D000429:Alcohol Oxidoreductases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: C000604566:AKR1B8 protein, mouse; D017382:Reactive Oxygen Species; D016264:Dextran Sulfate; D000429:Alcohol Oxidoreductases; C560505:Akr1b10 protein, mouse; D000074408:Aldo-Keto Reductases; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors