Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model.
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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DOI：
10.1016/j.jcmgh.2016.01.006
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发表时间：
2016-05
影响因子：
7.2
通讯作者：
Merlin D
中科院分区：
文献类型：
--
作者：
Viennois E;Ingersoll SA;Ayyadurai S;Zhao Y;Wang L;Zhang M;Han MK;Garg P;Xiao B;Merlin D
人肠肽转运蛋白 1 (hPepT1) 在健康结肠的小肠中表达水平较低，在炎症性肠病期间表达上调。 hPepT1 在小鼠结肠炎中发挥作用，人类研究表明慢性肠道炎症会导致结直肠癌（结肠炎相关癌；CAC）。因此，我们在此评估了 PepT1 在 CAC 中的作用。使用肠上皮细胞中 hPepT1 过表达（转基因 [TG]）或 PepT1（PepT1 敲除 [KO]）缺失的小鼠，并通过氧化偶氮甲烷/葡聚糖硫酸钠诱导 CAC。与野生型（WT）小鼠相比，TG 小鼠的肿瘤尺寸更大，肿瘤负荷增加，肠道炎症也增加。相反，PepT1-KO 小鼠的肿瘤数量和大小以及肠道炎症均显着减少。 TG 小鼠中增殖的隐窝细胞增加，而 PepT1-KO 小鼠中增殖的隐窝细胞减少。对人类结肠活检标本的分析显示，结直肠癌患者中 PepT1 的表达增加，表明 PepT1 可能是 CAC 治疗的靶点。使用 PepT1 转运的抗炎三肽 Lys-Pro-Val (KPV) 能够预防 WT 小鼠的癌变。当给予 PepT1-KO 小鼠时，KPV 没有引发在 WT 小鼠中观察到的任何对肿瘤发生的抑制作用。 PepT1 在人类结直肠肿瘤中高表达，并且其在小鼠中的过度表达和缺失分别增加和减少结肠炎相关肿瘤发生的观察结果表明，PepT1 是治疗结肠炎相关肿瘤发生的潜在治疗靶点。
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. 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. 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. 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.