Overexpression of Dicer in precursor lesions of lung adenocarcinoma
Overexpression of Dicer in precursor lesions of lung adenocarcinoma
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DOI：
10.1158/0008-5472.can-06-3533
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Dacic, Sanja
中科院分区：
文献类型：
--
作者：
Chiosea, Simion;Jelezcova, Elena;Dacic, Sanja
在非小细胞肺癌中描述了差异microRNA（mill）表达。然而，生物发生需要一组统称为miR机制的蛋白质。在所提出的多步骤癌变模型中，肺外周腺癌由非典型腺瘤性增生（AAH）和细支气管肺泡癌（BAC）等非侵袭性前驱病变发展而来。BAC和腺癌的基因阵列分析显示Dicer（小干扰RNA和mill功能的关键效应蛋白）和PACT的瞬时上调，以及沿着大多数编码miR机器蛋白的基因的下调。免疫组化显示，Dicer在AAH和BAC中表达上调，在浸润区和晚期腺癌中表达下调。一部分腺癌由于Dicer基因座的缺失而失去Dicer。扩大免疫组化和Western blot分析显示，Dicer在肺鳞癌（SCC）中的表达高于腺癌。与腺癌细胞系相比，SCC细胞系中RNA诱导沉默复合物的其他蛋白质（RISC; SND I，PACT和FXRI）也以更高的水平存在。总之，研磨机和RISC的化学计量取决于肺癌的组织学亚型，沿着AAH-BAC腺癌序列沿着变化，并且可以解释在肺癌中观察到的异常miR谱。在不同的组织学亚型和肺癌阶段的内源性研磨机的状态可能有助于预测未来的RNA干扰为基础的治疗的毒性和易感性。
Differential microRNA (mill) expression is described in nonsmall cell lung carcinoma. mill, biogenesis requires a set of proteins collectively referred to as the miR machinery. In the proposed multistep carcinogenesis model, peripheral adenocarcinoma of the lung develops from noninvasive precursor lesions known as atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC). The gene array analysis of BAC and adenocarcinoma showed a transient upregulation of Dicer (a key effector protein for small interfering RNA and mill function) and PACT along with down-regulation of most genes encoding miR machinery proteins. Immunohistochemically, Dicer was up-regulated in AAH and BAC and down-regulated in areas of invasion and in advanced adenocarcinoma. A fraction of adenocarcinomas lose Dicer as a result of deletions at the Dicer locus. Expanded immunohistochemical and Western blot analysis showed higher Dicer level in squamous cell carcinoma (SCC) of the lung when compared with adenocareinoma. Other proteins of the RNAinduced silencing complex (RISC; SND I, PACT, and FXRI) were also present at higher levels in a SCC cell line when compared with an adenocarcinoma cell line. In conclusion, the stoichiometry of mill machinery and RISC depends on histologic subtype of lung carcinoma, varies along the AAH-BACadenocarcinoma sequence, and might explain the observed abnormal miR profile in lung cancer. The status of the endogenous mill machinery in various histologic subtypes and stages of lung cancer may help to predict the toxicity of and susceptibility to future RNA interference-based therapy.