Critical Role of PepT1 in Promoting Colitis-Associated Cancer and Therapeutic Benefits of the Anti-inflammatory PepT1-Mediated Tripeptide KPV in a Murine Model

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• 作者：Emilie Viennois¹ ; ² ; ^{eviennois@gsu.edu" class="auth_mail" title="E-mail the corresponding author} ; Sarah A. Ingersoll¹ ; Saravanan Ayyadurai¹ ; Yuan Zhao¹ ; ³ ; Lixin Wang¹ ; ² ; Mingzhen Zhang¹ ; Moon K. Han¹ ; Pallavi Garg¹ ; Bo Xiao¹ ; Didier Merlin¹ ; ²
• 关键词：Colitis-Associated Cancer ; Intestinal Inflammation ; PepT1 ; KPV Peptide
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：2
• 期：3
• 页码：340-357
• 全文大小：4713 K

文摘

The human intestinal peptide transporter 1 (hPepT1), is expressed in the small intestine at low levels in the healthy colon and up-regulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have shown 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 (transgenic [TG]) or PepT1 (PepT1-knockout [KO]) deletion were used and CAC was induced by azoxymethane/dextran sodium sulfate.

Results

TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared with wild-type (WT) mice. Conversely, tumor number and size and intestinal inflammation were decreased significantly in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsy specimens showed 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 Lys-Pro-Val (KPV) 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.