title: Characterisation of colonic dysplasia-like epithelial atypia in murine colitis.
abstract: OBJECTIVE
  To determine if exacerbation of pre-existing chronic colitis in Winnie (Muc2mutant) mice induces colonic dysplasia.
  
  
  METHODS
  Winnie mice and C57BL6 as a genotype control, were administered 1% w/v dextran sulphate sodium (DSS) orally, followed by drinking water alone in week-long cycles for a total of three cycles. After the third cycle, mice were killed and colonic tissue collected for histological and immunohistochemical evaluation. Inflammation and severity of dysplasia in the colonic mucosa were assessed in H&E sections of the colon. Epithelial cell proliferation was assessed using Ki67 and aberrant β-catenin signalling assessed with enzyme-based immunohistochemistry. Extracted RNA from colonic segments was used for the analysis of gene expression using real-time quantitative PCR. Finally, the distribution of Cxcl5 was visualised using immunohistochemistry.
  
  
  RESULTS
  Compared to controls, Winnie mice exposed to three cycles of DSS displayed inflammation mostly confined to the distal-mid colon with extensive mucosal hyperplasia and regenerative atypia resembling epithelial dysplasia. Dysplasia-like changes were observed in 100% of Winnie mice exposed to DSS, with 55% of these animals displaying changes similar to high-grade dysplasia, whereas high-grade changes were absent in wild-type mice. Occasional penetration of the muscularis mucosae by atypical crypts was observed in 27% of Winnie mice after DSS. Atypical crypts however displayed no evidence of oncogenic nuclear β-catenin accumulation, regardless of histological severity. Expression ofCav1,Trp53was differentially regulated in the distal colon of Winnie relative to wild-type mice. Expression ofMycandCcl5was increased by DSS treatment in Winnie only. Furthermore, increasedCcl5expression correlated with increased complexity in abnormal crypts. While no overall difference inCxcl5mucosal expression was observed between treatment groups, epithelial Cxcl5 protein appeared to be diminished in the atypical epithelium.
  
  
  CONCLUSIONS
  Alterations to the expression ofCav1,Ccl5,MycandTrp53in the chronically inflamed Winnie colon may influence the transition to dysplasia.
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Sarron
authors.initials: S
authors.lastname: Randall-Demllo
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Ruchira
authors.initials: R
authors.lastname: Fernando
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Terry
authors.initials: T
authors.lastname: Brain
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Sukhwinder Singh
authors.initials: SS
authors.lastname: Sohal
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cook
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Nuri
authors.initials: N
authors.lastname: Guven
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Dale
authors.initials: D
authors.lastname: Kunde
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Spring
authors.affiliation: Sarron Randall-Demllo, Sukhwinder Singh Sohal, Dale Kunde, Rajaraman Eri, School of Health Sciences, University of Tasmania, Launceston, Launceston TAS 7250, Australia.
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Eri
mesh_terms: D000818:Animals; D001835:Body Weight; D054365:Chemokine CXCL5 / Q000378:metabolism; D003092:Colitis / Q000473:pathology*; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology*; D016264:Dextran Sulfate; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D019394:Ki-67 Antigen; D051176:beta Catenin; D012313:RNA; D016264:Dextran Sulfate
keywords: Colitis; Colon; Dextran sulphate sodium; Dysplasia; Mice; Mucin-2