Liu Xiao-Qiong, Chen Han-Kui, Zhang Xiao-Shi, Pan Zhi-Gang, Li Ang, Feng Qi-Sheng, Long Qing-Xin, Wang Xun-Zhang, Zeng Yi-Xin
Cancer Center, Sun Yat-sen University, Guangzhou, China.
Int J Cancer. 2003 Aug 10;106(1):60-5. doi: 10.1002/ijc.11166.
Nonrandom allelic loss on chromosome 3p is a common event in nasopharyngeal carcinoma (NPC) with the implication that certain tumor suppressor gene(s) in this region are involved in the pathogenesis of these tumors. The BLU gene, located at 3p21.3, has recently been identified as a candidate tumor suppressor gene due to the occurrence of missense mutations and loss of its expression in lung cancer. To investigate the involvement of BLU gene in NPC, we examined both genetic and epigenetic changes of BLU in NPC primary tumors and cell lines. No pathogenic mutations were detected in the entire coding region of this gene in 45 primary NPC tumors and 5 NPC cell lines. While BLU was expressed in 100% (15 of 15) of noncancerous nasopharyngeal epithelia, its transcripts were missing in all 5 NPC cell lines, and absent or reduced mRNA levels were observed in 78% (28 of 36) of the primary tumors. In the NPC cell lines, loss of BLU expression correlated with hypermethylation of the CpG island promoter sequence, and expression was restored after treatment with 5'-aza-2'-deoxycytidine. Methylation specific PCR analysis revealed that the BLU promoter was highly methylated in 74% (17 of 23) of primary tumors in which BLU was downregulated, whereas only 2 of 9 non-neoplastic nasopharyngeal epithelia exhibited hypermethylation in the BLU promoter region. The high incidence of BLU alterations suggests that it may be one of the critical tumor suppressor genes on chromosome 3p21.3 involved in the development of NPC.
3号染色体短臂上的非随机等位基因缺失是鼻咽癌（NPC）中的常见事件，这意味着该区域的某些肿瘤抑制基因参与了这些肿瘤的发病机制。位于3p21.3的BLU基因，最近由于在肺癌中发生错义突变并丧失其表达而被鉴定为候选肿瘤抑制基因。为了研究BLU基因在鼻咽癌中的作用，我们检测了鼻咽癌原发肿瘤和细胞系中BLU基因的遗传和表观遗传学变化。在45例原发性鼻咽癌肿瘤和5个NPC细胞系中，未在该基因的整个编码区检测到致病突变。虽然BLU在100%（15例中的15例）的非癌性鼻咽上皮中表达，但其转录本在所有5个NPC细胞系中均缺失，并且在78%（36例中的28例）的原发性肿瘤中观察到mRNA水平缺失或降低。在NPC细胞系中，BLU表达的丧失与CpG岛启动子序列的高甲基化相关，并且在用5'-氮杂-2'-脱氧胞苷处理后表达得以恢复。甲基化特异性PCR分析显示，在74%（23例中的17例）BLU下调的原发性肿瘤中，BLU启动子高度甲基化，而9例非肿瘤性鼻咽上皮中只有2例在BLU启动子区域表现出高甲基化。BLU改变的高发生率表明它可能是3p21.3染色体上参与鼻咽癌发生发展的关键肿瘤抑制基因之一。
