Dietary diindolylmethane suppresses inflammation-driven lung squamous cell carcinoma in mice.
Dietary diindolylmethane suppresses inflammation-driven lung squamous cell carcinoma in mice.
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膳食二吲哚甲烷可抑制小鼠炎症引起的肺鳞状细胞癌。
DOI：
10.1158/1940-6207.capr-14-0245
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Kassie,Fekadu
中科院分区：
文献类型：
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作者：
Song,JungMin;Qian,Xuemin;Teferi,Fitsum;Pan,Jing;Wang,Yian;Kassie,Fekadu
已知肺部的炎症性疾病如慢性阻塞性肺病（COPD）会增加肺癌的风险，特别是肺鳞状细胞癌（LSCC）。在本研究中，我们开发了一种炎症驱动的LSCC小鼠模型，该模型由N-亚硝基-三氯乙基脲（NTCU）诱导并由脂多糖（LPS）（烟草和烟草烟雾中含有的一种有效的促炎剂）增强，并确定了BioResponse二吲哚甲烷（DIM）在同一模型中的化学预防作用。与单独用NTCU治疗的小鼠相比，用NTCU和LPS组合治疗的小鼠具有9倍的LSCC细支气管数目增加。此外，与单独用LPS处理的小鼠相比，用NTCU加LPS处理的小鼠显示炎性细胞因子IL 1 α、IL 6和TNFα的表达显著增加（所有三种均增加约7倍）。与增加的细胞因子基因表达平行，NTCU + LPS处理组在肺中表现出显著增强的NF-κB、STAT 3、ERK、p-38和Akt的活化，p53、考克斯-2和Mcl-1的表达，以及NF-κB-和STAT 3-DNA结合。对接受NTCU加LPS治疗的小鼠进行DIM（10 μmol/g饲料或2，460 ppm）饮食给药可将LSCC的发病率降低2倍，抑制促炎和前致癌蛋白的活化/表达以及NF-κB和STAT 3-DNA结合，但不抑制细胞因子和p53的表达。这项研究强调了我们的小鼠模型在鉴定用于人类LSCC的化学预防的有前景的药物或膳食剂方面的潜在意义，并且DIM是临床肺癌化学预防试验的非常好的候选者。©2014 AACR.
Inflammatory conditions of the lung such as chronic obstructive pulmonary disease (COPD) are known to increase lung cancer risk, particularly lung squamous cell carcinoma (LSCC). In the present study, we developed a mouse model of inflammation-driven LSCC that was induced byN-nitroso-trischloroethylurea (NTCU) and enhanced by lipopolysaccharide (LPS), a potent proinflammatory agent contained in tobacco and tobacco smoke, and determined the chemopreventive effects of BioResponse diindolylmethane (DIM) in the same model. Compared with mice treated with NTCU alone, mice treated with the combination of NTCU and LPS had a 9-fold increase in the number of bronchioles with LSCC. Also, compared with mice treated with LPS alone, mice treated with NTCU plus LPS showed significantly increased expression of the inflammatory cytokines IL1α, IL6, and TNFα (all three increased about 7-fold). Parallel to the increased cytokine gene expression, the NTCU plus LPS-treated group exhibited significantly enhanced activation of NF-κB, STAT3, ERK, p-38, and Akt, expression of p53, COX-2, and Mcl-1, and NF-κB- and STAT3-DNA binding in the lung. Dietary administration of DIM (10 μmol/g diet or 2,460 ppm) to mice treated with NTCU plus LPS reduced the incidence of LSCC by 2-fold, suppressed activation/expression of proinflammatory and procarcinogenic proteins and NF-κB- and STAT3-DNA binding, but not the expression of cytokines and p53. This study highlights the potential significance of our mouse model to identify promising drugs or dietary agents for the chemoprevention of human LSCC and that DIM is a very good candidate for clinical lung cancer chemoprevention trials.Cancer Prev Res; 8(1); 77–85. ©2014 AACR.