Shen Yi, Ma Jun, Yan Ruilan, Ling Hongyan, Li Xiaoning, Yang Wancai, Gao John, Huang Chenfei, Bu Yiwen, Cao Yu, He Yingchun, Wan Laxiang, Zu Xuyu, Liu Jianghua, Huang Mei Chris, Stenson William F, Liao Duan-Fang, Cao Deliang
Department of Medical Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
Clin Cancer Res. 2015 Mar 15;21(6):1466-76. doi: 10.1158/1078-0432.CCR-14-2072. Epub 2014 Dec 23.
Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC.
Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8(-/-)) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors.
AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8(-/-) mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8(-/-) mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8(-/-) mice than in wild-type mice. Palpable masses were seen in the AKR1B8(-/-) mice only, not in wild-type.
AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases.
溃疡性结肠炎及结肠炎相关结直肠癌（CAC）是严重的健康问题，但病因病理因素仍不明确。醛酮还原酶1B10（AKR1B10）在结肠上皮中特异性表达，但在结直肠癌中表达下调。本研究旨在探讨AKR1B10在溃疡性结肠炎和CAC中的致病作用。
收集溃疡性结肠炎和CAC活检组织（石蜡包埋切片）及冷冻组织以检测AKR1B10表达。制备醛酮还原酶1B8（人类AKR1B10的直系同源物）基因敲除（AKR1B8(-/-)）小鼠，以评估其在低剂量（2%）葡聚糖硫酸钠（DSS）诱导的慢性结肠炎及相关发育异常病变的易感性和严重程度中的作用。采用全基因组外显子测序分析DSS诱导的结肠炎和肿瘤中的DNA损伤情况。
超过90%的溃疡性结肠炎和CAC组织中AKR1B10表达明显降低。AKR1B8缺陷导致丁酸酯脂质合成减少及结肠上皮细胞增殖减弱。DSS处理的AKR1B8(-/-)小鼠结肠上皮损伤修复受损，出血、炎症和溃疡更严重。这些AKR1B8(-/-)小鼠氧化应激和DNA损伤更严重，与野生型小鼠相比，AKR1B8(-/-)小鼠发育异常更频繁且程度更高。仅在AKR1B8(-/-)小鼠中可触及肿块，野生型小鼠中未出现。
AKR1B8是结肠上皮增殖和损伤修复以及溃疡性结肠炎和CAC发病机制中的关键蛋白，是这些疾病的新致病因素。
