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Nrf2基因沉默对小鼠氧化应激相关肠道癌变的影响。

Effects of Nrf2 silencing on oxidative stress-associated intestinal carcinogenesis in mice.

作者信息

Yokoo Yuh, Kijima Aki, Ishii Yuji, Takasu Shinji, Tsuchiya Takuma, Umemura Takashi

机构信息

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.

出版信息

Cancer Med. 2016 Jun;5(6):1228-38. doi: 10.1002/cam4.672. Epub 2016 Feb 21.

DOI:10.1002/cam4.672
PMID:26899729
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4924381/
Abstract

To assess the risk of colorectal cancer in humans with inactivation of NRF2, Nrf2-proficient (Nrf2(+/+) ) and -deficient (Nrf2(-/-) ) mice were exposed to potassium bromate (KBrO3 ) at concentrations of 750 or 1500 ppm for 52 weeks. Neoplastic proliferative lesions were observed in the small intestine and exhibited accumulations of β-catenin and cyclin D1. The lesions had characteristics similar to those in experimental models of human hereditary colorectal cancer. An additional 13-week study was performed to examine the role of Nrf2 in the effects of oxidative stress. Significant increase in combined incidences of preneoplastic and neoplastic lesions in Nrf2(-/-) mice administered high-dose KBrO3 . In the short-term study, although 8-hydroxydeoxyguanosine (8-OHdG) levels in the epithelial DNA of Nrf2(-/-) mice at the high dose were significantly lower than those of the corresponding Nrf2(+/+) mice, the difference was very small. mRNA levels of Nrf2-regulated genes were increased in Nrf2(+/+) mice. Overexpression of cyclooxygenase 2 (COX2) and increased numbers of proliferating cell nuclear antigen (PCNA)-positive cells in the jejunal crypts were observed in Nrf2(-/-) mice administered high-dose KBrO3 . Overall, these data suggested that individuals having single-nucleotide polymorphisms in NRF2 may have a risk of colorectal cancer to some extent.

摘要

为评估NRF2失活的人类患结直肠癌的风险，将Nrf2功能正常（Nrf2(+/+)）和功能缺陷（Nrf2(-/-)）的小鼠暴露于浓度为750或1500 ppm的溴酸钾（KBrO3）中52周。在小肠中观察到肿瘤性增殖性病变，并出现β-连环蛋白和细胞周期蛋白D1的积累。这些病变具有与人类遗传性结直肠癌实验模型相似的特征。进行了一项为期13周的额外研究，以检验Nrf2在氧化应激影响中的作用。给予高剂量KBrO3的Nrf2(-/-)小鼠中，癌前病变和肿瘤性病变的合并发生率显著增加。在短期研究中，虽然高剂量下Nrf2(-/-)小鼠上皮DNA中的8-羟基脱氧鸟苷（8-OHdG）水平显著低于相应的Nrf2(+/+)小鼠，但差异非常小。Nrf2(+/+)小鼠中Nrf2调控基因的mRNA水平升高。在给予高剂量KBrO3的Nrf2(-/-)小鼠中，观察到空肠隐窝中环氧合酶2（COX2）的过表达和增殖细胞核抗原（PCNA）阳性细胞数量增加。总体而言，这些数据表明，NRF2存在单核苷酸多态性的个体可能在一定程度上有患结直肠癌的风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/478c2a26d904/CAM4-5-1228-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/6ca76d4a7fc8/CAM4-5-1228-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/966f6879ca6a/CAM4-5-1228-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/4d02cc0a3db9/CAM4-5-1228-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/1445efcfbbda/CAM4-5-1228-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/694e1e27c0f3/CAM4-5-1228-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/478c2a26d904/CAM4-5-1228-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/6ca76d4a7fc8/CAM4-5-1228-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/966f6879ca6a/CAM4-5-1228-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/4d02cc0a3db9/CAM4-5-1228-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/1445efcfbbda/CAM4-5-1228-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/694e1e27c0f3/CAM4-5-1228-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b81/4924381/478c2a26d904/CAM4-5-1228-g006.jpg

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