Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3
Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3
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DOI：
10.1038/77083
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发表时间：
2000-07-01
期刊：
影响因子：
30.8
通讯作者：
Pfeifer, GP
中科院分区：
文献类型：
--
作者：
Dammann, R;Li, C;Pfeifer, GP
3号染色体短臂处的等位基因丢失是肺癌发病机制中最常见和最早的事件之一，并且在超过90%的小细胞肺癌（SCLC）和50-80%的非小细胞肺癌（1，2）（NSCLC）中观察到。频繁和早期的杂合性丢失和纯合性缺失的存在表明3p21.3区域在肿瘤发生中的关键作用（2-4），3p21.3中常见的纯合性缺失区域缩小到120 kb（参考文献5）。几个假定的肿瘤抑制基因位于3 p21的特点，但这些基因似乎都没有改变肺癌。在这里，我们描述了人类RAS效应同源物（RASSF 1）位于最小纯合缺失的120 kb区域的克隆和表征。我们确定了三个转录本，A，B和C，来自选择性剪接和启动子的使用。主要转录本A和C在所有正常组织中表达。转录本A在分析的所有SCLC细胞系和几种其他癌细胞系中缺失。表达的缺失与RASSF 1A的CpG岛启动子序列的甲基化相关。60例原发性肺肿瘤中有24例（40%）的启动子高度甲基化，41例分析的肿瘤中有4例携带错义突变。在肺癌细胞中转录本A的重新表达减少了集落形成，抑制了锚定非依赖性生长，并抑制了裸鼠肿瘤形成。这些特征表明RASSF 1A可能是一种肺肿瘤抑制基因。
Allelic loss at the short arm of chromosome 3 is one of the most common and earliest events in the pathogenesis of lung cancer, and is observed in more than 90% of small-cell lung cancers (SCLCs) and in 50-80% of non-small-cell lung cancers(1,2) (NSCLCs). Frequent and early loss of heterozygosity and the presence of homozygous deletions suggested a critical role of the region 3p21.3 in tumorigenesis(2-4) and a region of common homozygous deletion in 3p21.3 was narrowed to 120 kb (ref. 5). Several putative tumour-suppressor genes located at 3p21 have been characterized, but none of these genes appear to be altered in lung cancer. Here we describe the cloning and characterization of a human RAS effector homologue (RASSF1) located in the 120-kb region of minimal homozygous deletion. We identified three transcripts, A, B and C, derived from alternative splicing and promoter usage. The major transcripts A and C were expressed in all normal tissues. Transcript A was missing in all SCLC cell lines analysed and in several other cancer cell lines. loss of expression was correlated with methylation of the CpG-island promoter sequence of RASSF1A. The promoter was highly methylated in 24 of 60 (40%) primary lung tumours, and 4 of 41 tumours analysed carried missense mutations. Re-expression of transcript A in lung carcinoma cells reduced colony formation, suppressed anchorage-independent growth and inhibited tumour formation in nude mice. These characteristics indicate a potential role for RASSF1A asa lung tumour suppresor gene.