Epigenetic inactivation of RAS association domain family protein 1 (RASSF1A) in malignant cutaneous melanoma.
Epigenetic inactivation of RAS association domain family protein 1 (RASSF1A) in malignant cutaneous melanoma.
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发表时间：
2003-04
期刊：
影响因子：
11.2
通讯作者：
Mia Spugnardi;S. Tommasi;R. Dammann;G. Pfeifer;D. Hoon
中科院分区：
文献类型：
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作者：
Mia Spugnardi;S. Tommasi;R. Dammann;G. Pfeifer;D. Hoon
最近的研究结果表明，Ras效应同源基因被称为Ras相关结构域家族1（RASSF 1）基因，这是一个潜在的人类肿瘤抑制基因位于染色体3p21.3的失活。RASSF 1A基因的一个主要转录本CpG岛启动子区的超甲基化在多种肿瘤的发病机制中起着关键作用。除癌外，对RASSF 1A在肿瘤中失活的分析有限。使用甲基化特异性PCR研究了转移性皮肤黑色素瘤中RASSF 1A CpG岛两个区域的超甲基化;区域1位于上游，区域2位于RASSF 1A转录物开放阅读框架的第一个外显子（1 α）内。检查了11个黑素瘤细胞系和44个黑素瘤肿瘤。RASSF 1A CpG岛启动子区1在7个（64%）细胞系和18个（41%）肿瘤中检测到甲基化，2在9个（82%）细胞系和22个（50%）肿瘤中检测到甲基化。总体而言，在55%的黑色素瘤肿瘤中检测到RASSF 1A基因超甲基化。在正常皮肤组织或健康供体淋巴细胞中未检测到甲基化。在启动子区域1显示甲基化的所有细胞系也在启动子区域2甲基化。两个CpG岛区域的超甲基化与RASSF 1A基因的无表达相关。RASSF 1A转录本经5 '-氮杂-2'-脱氧胞苷处理后可在细胞系中重新表达。我们的研究结果表明，RASSF 1A基因是关闭在一个显着的黑色素瘤和CpG启动子区域的超甲基化可能发挥作用，在恶性黑色素瘤的RASSF 1A基因的转录失活。
Recent findings have shown the inactivation of a Ras effector homologue gene referred to as the Ras association domain family 1 (RASSF1) gene, which is a potential human tumor suppressor gene located on chromosome 3p21.3. Hypermethylation of the CpG island promoter region of a major alternative transcript of this gene, RASSF1A, has been suggested to play a key role in pathogenesis of various carcinomas. There is limited analysis of inactivation of RASSF1A in tumors other than carcinomas. Hypermethylation of two regions of the RASSF1A CpG island was investigated in metastatic cutaneous melanomas using methylation-specific PCR; region 1 is located upstream, and region 2 is located within the first exon (1alpha) of the open reading frame of the RASSF1A transcript. Eleven melanoma cell lines and 44 melanoma tumors were examined. Methylation of RASSF1A CpG island promoter region 1 was detected in 7 (64%) cell lines and 18 (41%) tumors, and methylation of region 2 was detected in 9 (82%) cell lines and 22 (50%) tumors. Overall, RASSF1A gene hypermethylation was detected in 55% of the melanoma tumors. No methylation was detected in normal skin tissues or healthy donor lymphocytes. All cell lines that showed methylation at promoter region 1 were also methylated at promoter region 2. Hypermethylation of both CpG island regions correlated with no expression of the RASSF1A gene. RASSF1A transcripts could be reexpressed in cell lines after treatment with 5'-aza-2'-deoxycytidine. Our findings indicate that the RASSF1A gene is turned off in a significant number of melanomas and that CpG promoter region hypermethylation may play a role in the transcriptional inactivation of the RASSF1A gene in malignant melanoma.