Abstract
Abstract
Background: Ulcerative colitis (UC) is a major clinically defined form of inflammatory bowel disease which affects individuals throughout a life and associates with an increased risk of developing colorectal cancer. Aldo-keto reductase 1B10 (AKR1B10), isolated by our laboratory, is a novel monomeric NADPH-dependent enzyme with reductive activity towards reactive carbonyls. AKR1B10 also acts as a novel regulator of de novo fatty acid synthesis and lipid metabolism via regulating acetyl-CoA carboxylase-α (ACCA) stability. AKR1B10 is primarily expressed in normal human intestines, but lost in colorectal cancer and predisposition conditions, such as UC and adenomatous polyps, suggesting its pathogenic role in the these diseases.
Aldo-keto reductase 1B8 (AKR1B8) is the mouse ortholog of human AKR1B10, having the similar enzyme activity to α,β-unsaturated carbonyls and capability of regulating fatty acid synthesis and lipid metabolism in mice. Thereby, we generated an AKR1B8 knockout (-/-) mouse strain to understand the etiopathogenic role of AKR1B10/8 in the UC and associated colorectal cancer to
Methods: AKR1B8 -/- mouse strain was produced by homozygous recombination. Dextran sulfate sodium (DSS) was utilized to induce colitis and associated colorectal tumors. In detail, AKR1B8 -/- mice were fed with 2% DSS in drink water for four cycles (e.g., 7 days DSS, 14 days water). Inflammatory activity and masses were recorded, and histopathology of chronic colitis, crypt architecture, and micro-neoplastic lesions was examined. Profiles of multiple cytokines and reactive oxidative species in colonic mucosa were estimated. Potential DNA mutations were identified using whole Exome sequencing.
Results: Targeted disruption of AKR1B8 disturbed the self-renewal and injury recovery of colonic cryptic cells due to decrease in lipid synthesis from butyrate. AKR1B8 deficient mice are highly susceptible to colitis induced by DSS at 2% and to carbonyl and oxidative DNA damage, leading to colitis-associated tumorigenesis and malignant progression. Histopathological studies showed that AKR1B8 -/- mice suffered severe inflammatory lesions and high-grade dysplasia. Importantly, visible large masses were seen in AKR1B8 -/- mice, but not in wild type that underwent the same DSS treatment. Furthermore, 269 gene variants (in exons) were identified uniquely in AKR1B8 -/- colitis mucosa and tumors, not in WT colitis. Among them, 20 genes were mutated in colitis only and 28 genes in tumors alone. A total of 221 genes were mutated in both AKR1B8 -/- colitis mucosa and tumors. These gene mutants may represent the DNA damage that drives the malignant transition of colitis.
Conclusions: AKR1B8 (AKR1B10 in humans) is a critical protein that regulates the dynamic homeostasis of self-renewal and barrier function of colonic epithelium. AKR1B8 deficiency in colonic epithelium is a critical etiopathogenic factor of UC and its tumorigenic transformation.
Note: This abstract was not presented at the meeting.
Citation Format: Yi Shen, Jun Ma, Ruilan Yan, Hongyan Ling, Xiaoning Li, Wancai Yang, John Gao, Yiwen Bu, Ahmed Alsalman, Cheifei Huang, Yu Cao, Shuangbai Zhou, Laxiang Wan, Yingchun He, Zhiqi Wang, Ali Khazaal, Mei Chris Huang, Duan-Fang Liao, Deliang Cao. Impaired self-renewal and colitis susceptibility of colonic mucosa in mice lacking AKR1B8. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5348. doi:10.1158/1538-7445.AM2014-5348