Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice
| Autor: | Deliang Cao, John Gao, Xiaoning Li, Duan-Fang Liao, Yi Shen, Hongyan Ling, Wancai Yang, Mei Chris Huang, Ruilan Yan, Jun Ma, Yiwen Bu, Yingchun He, William F. Stenson, Xuyu Zu, Chenfei Huang, Laxiang Wan, Jianghua Liu, Yu Cao |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Colorectal cancer Colon Aldo-Keto Reductases Inflammation Butyrate Article Pathogenesis Mice Intestinal mucosa Medicine Animals Humans Colitis Intestinal Mucosa Cell Proliferation Mice Knockout Base Sequence business.industry Dextran Sulfate Oxidoreductases Acting on Aldehyde or Oxo Group Donors Cancer Epithelial Cells Sequence Analysis DNA medicine.disease Ulcerative colitis digestive system diseases Mice Inbred C57BL Alcohol Oxidoreductases Disease Models Animal Oxidative Stress Cell Transformation Neoplastic Oncology Colitis Ulcerative medicine.symptom business Colorectal Neoplasms Reactive Oxygen Species DNA Damage |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 21(6) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 21(6); 1466–76. ©2014 AACR. |
| Databáze: | OpenAIRE |
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