A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice.
A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice.
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DOI：
10.1158/1940-6207.capr-10-0023
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
You M
中科院分区：
文献类型：
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作者：
Tichelaar JW;Yan Y;Tan Q;Wang Y;Estensen RD;Young MR;Colburn NH;Yin H;Goodin C;Anderson MW;You M
肺癌是美国和世界范围内癌症死亡的主要原因。因此，确定参与肺肿瘤发生的关键调控机制和分子机制对于增加我们对这种疾病的了解至关重要，并最终可能导致靶向治疗以改善预防和治疗。激活蛋白(AP)-1转录因子家族成员的诱导在人类非小细胞肺癌中已被描述。AP-1的激活可以刺激或抑制多个基因靶点的转录，最终导致细胞增殖增加，抑制细胞凋亡。在目前的研究中，我们证明了AP-1在致癌物诱导的小鼠肺肿瘤中的诱导作用，并与周围正常肺组织进行了比较。然后，我们使用了一个转基因小鼠模型，直接在肺上皮细胞中有条件地表达显性负c-jun突变体TAM67，以确定抑制AP-1对小鼠肺肿瘤形成的影响。与正常肺组织中AP-1活性低一致，TAM67在成年小鼠肺中的表达没有观察到影响。在化学诱导的小鼠肺肿瘤模型中，TAM67降低了肿瘤数量和总的肺肿瘤负荷。与较低级别的病变相比，对肿瘤负担的抑制作用最显著。我们的结果支持AP-1是小鼠肺肿瘤发生的关键调节因子的概念，并确认AP-1依赖的转录是防止肺癌进展的潜在靶点。
Lung cancer is the leading cause of cancer mortality in the US and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein (AP)-1 transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study we demonstrate induction of AP-1 in carcinogen induced mouse lung tumors compared to surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared to lower grade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis and identify AP-1 dependent transcription as a potential target to prevent lung tumor progression.