Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
PLoS Med. 2010 Jul 27;7(7):e1000315. doi: 10.1371/journal.pmed.1000315.
Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes--adenocarcinoma (AC) and squamous cell carcinoma (SqCC)--respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy. Please see later in the article for the Editors' Summary.
传统上，非小细胞肺癌在系统治疗方面被视为单一疾病实体。新出现的证据表明，主要亚型——腺癌（AC）和鳞状细胞癌（SqCC）——对治疗的反应不同。鉴定这些肿瘤类型之间的分子差异将对设计新的治疗方法产生重大影响，从而改善治疗结果。
我们使用整合基因组学方法，结合高分辨率比较基因组杂交和基因表达微阵列谱，比较 AC 和 SqCC 肿瘤，以揭示 DNA 水平的改变，以及在肺癌亚型发展过程中选择的相应基因转录变化。通过对多个独立队列的临床肿瘤样本（>330 个）、吸烟者中通过支气管刷获得的正常肺组织和支气管上皮细胞进行分析，我们发现 BRF2 的过表达，这是 8p12 染色体上的一个基因，是 SqCC 肺癌发展的特异性基因。BRF2 基因编码 RNA 聚合酶 III（Pol III）转录起始因子，其遗传激活与涉及细胞生长的基本过程的小核 RNA（snRNA）的表达增加有关，例如 RNA 剪接。BRF2 在人支气管上皮细胞中的异位表达诱导了转化表型，并证明了下游致癌效应，而 RNA 干扰（RNAi）介导的敲低抑制了 BRF2 过表达的 SqCC 细胞的生长和集落形成，但对 AC 细胞没有影响。在 >35%的原位早期支气管癌以及发育不良病变中频繁激活 BRF2，这表明 BRF2 表达是该细胞谱系癌症发展的早期事件。
据我们所知，这是第一项研究表明，8p12 染色体上的基因局灶扩增在疾病的鳞状细胞谱系特异性中起关键作用。我们的数据表明，BRF2 的遗传激活代表了 SqCC 肺癌发生的一种独特机制，通过增加 Pol III 介导的转录。它可以作为肺 SqCC 的标志物，并为治疗提供新的靶点。请在文章后面查看编辑摘要。
