title: Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model.
abstract: OBJECTIVE
  The human intestinal peptide transporter 1, hPepT1, is expressed in the small intestine at low levels in the healthy colon and upregulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have demonstrated that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC). Hence, we assessed here the role of PepT1 in CAC.
  
  
  METHODS
  Mice with hPepT1 overexpression in intestinal epithelial cells (TG) or PepT1 (PepT1-KO) deletion were used and CAC was induced by AOM/DSS.
  
  
  RESULTS
  TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared to WT mice. Conversely, tumor number and size and intestinal inflammation were significantly decreased in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsies revealed an increased expression of PepT1 in patients with colorectal cancer, suggesting that PepT1 might be targeted for the treatment of CAC. The use of an anti-inflammatory tripeptide KPV (Lys-Pro-Val) transported by PepT1 was able to prevent carcinogenesis in WT mice. When administered to PepT1-KO mice, KPV did not trigger any of the inhibitory effect on tumorigenesis observed in WT mice.
  
  
  CONCLUSIONS
  The observations that pepT1 was highly expressed in human colorectal tumor and that its overexpression and deletion in mice increased and decreased colitis associated tumorigenesis, respectively, suggest that PepT1 is a potential therapeutic target for the treatment of colitis associated tumorigenesis.
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA; Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Viennois
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Ingersoll
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA; Department of Gastroenterology, Zhongshan Hospital, Fudan University, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA; Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Moon Kwon
authors.initials: MK
authors.lastname: Han
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Garg
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Institute for Biomedical Sciences, Center Diagnostics and Therapeutics, Georgia State University, Atlanta, GA; Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
keywords: Colitis-associated cancer; Intestinal inflammation; KPV peptide; PepT1