Genetic and epigenetic alterations of BRG1 promote oral cancer development.
Genetic and epigenetic alterations of BRG1 promote oral cancer development.
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DOI：
10.3892/ijo.26.1.201
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发表时间：
2005
影响因子：
5.2
通讯作者：
E. Gunduz;M. Gunduz;M. Ouchida;H. Nagatsuka;L. Beder;H. Tsujigiwa;K. Fukushima;K. Nishizaki;K. S
中科院分区：
文献类型：
--
作者：
E. Gunduz;M. Gunduz;M. Ouchida;H. Nagatsuka;L. Beder;H. Tsujigiwa;K. Fukushima;K. Nishizaki;K. S
杂合缺失（LOH）分析是一种灵敏的检测特定染色体区域缺失的方法，该区域被认为含有肿瘤抑制基因（TSG）。先前对各种人类癌症的等位型分析表明，在染色体19p13区域至少存在一个TSG。BRG1是SWI/SNF复合体蛋白的一个成员，位于19p13.2，功能分析表明它是不同类型人类癌症的候选TSG。我们使用6个微卫星标记检测了39例口腔癌中19p13区域的LOH，发现39例样本中有25例（64%）存在等位基因缺失。BRG1位点附近的微卫星标记显示肿瘤样品中LOH最高。为了阐明BRG1基因在口腔癌发生中的作用，我们检查了其在肿瘤样本中的突变状态。由于BRG1基因在口腔癌中未检测到突变，我们检测了mRNA的表达水平。定量RT-PCR分析令人惊讶地显示，与匹配的正常样本相比，62%的原发肿瘤中BRG1 mRNA的表达增加。由于BRG1和另一个与BRG1高度同源的SWI/SNF成员BRM的功能可能相互关联，我们还在相同的样本中检测了BRM mRNA的表达。在大多数样本中，BRG1和BRM的表达方向变化与报道的人类癌细胞系数据一致。一个重要的发现是，在大多数肿瘤样本中，BRG1的另一种框架剪接形式（包括外显子26）的表达选择性地减少或丢失。BRG1蛋白独特的33个氨基酸序列与异质核核糖核蛋白E具有非常高的同源性，可能通过修饰转录后调控影响BRG1的功能和水平。这些发现提示BRG1的遗传和表观遗传改变可能在口腔癌的发展中起作用。
Loss of heterozygosity (LOH) analysis is a sensitive method to detect deletions of specific chromosome regions which are considered to harbor of putative tumor suppressor gene (TSG)s. Previous allelotype analyses in various human cancers suggested the presence of at least one TSG in chromosome 19p13 region. Functional analysis of BRG1, a member of SWI/SNF complex proteins, located at 19p13.2, suggested it to be a candidate TSG in different types of human cancers. We examined LOH at 19p13 region in 39 oral cancers by using six microsatellite markers and found allelic deletion in 25 of 39 (64%) samples. A microsatellite marker near BRG1 locus showed the highest LOH in tumor samples. To clarify the role of BRG1 gene in oral carcinogenesis, we checked its mutation status in tumor samples. As mutation of the BRG1 gene was not detected in oral cancers, we examined the mRNA expression level. Quantitative RT-PCR analysis surprisingly demonstrated increased expression of BRG1 mRNA in 62% of primary tumors as compared with that of matched normal samples. Since functions of BRG1 and BRM, another member of SWI/SNF highly homologous to BRG1, may be interrelated, we also examined BRM mRNA expression in the same samples. In most samples, the expressions of BRG1 and BRM changed in the same direction consistent with reported data on human cancer cell lines. An important finding is that expression of an alternative in frame splicing form of BRG1 which includes exon 26 is selectively decreased or lost in most tumor samples. This unique 33 amino-acid sequence of BRG1 protein shows very high homology with heterogeneous nuclear ribonucleoprotein E and may affect the function and level of BRG1 through modifications on post-transcriptional control. All these findings suggest that the genetic and epigenetic alterations of BRG1 may have a role in oral cancer development.