低水平p16INK4a和p15INK4b mRNA表达及其CpG岛甲基化与人类肝细胞癌发生的相关性。
Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis.
作者信息
Qin Yang, Liu Jian-Yu, Li Bo, Sun Zhi-Lin, Sun Ze-Fang
机构信息
Department of Biochemistry and Molecular Biology, School of Preclinical and Forensic Medicine, West China Medical Center, Sichuan University, Chengdu, 610041, Sichuan Province, China.
出版信息
World J Gastroenterol. 2004 May 1;10(9):1276-80. doi: 10.3748/wjg.v10.i9.1276.
AIM
To study the significance of p16 and p15 transcription suppression with hypermethylation of their genes' 5'CpG islands during human hepatocellular carcinogenesis.
METHODS
The mRNA expression levels of p16 and p15 genes were evaluated in cancerous, para-cancerous and non-cancerous tissues of 20 HCC, 3 normal liver tissues from 3 accidentally died healthy adults using semi-quantitatively Northern blot. The methylation status was also assessed with methylation specific PCR.
RESULTS
p16 mRNA expression level was decreased in the cancerous tissues in 60% (12/20) of HCC patients, of which 2 cases had no p16 mRNA detected, 5 cases (25%) displayed variation in the order of cancerous<para-cancerous<non-cancerous liver tissues. p15 mRNA expression level was decreased in the cancerous tissues in 50% (10/20) HCC patients, of which one case had no p15 mRNA detected, 4 cases (20%) displayed variation in the order of cancerous<para-cancerous<non-cancerous liver tissues. In cancerous, para-cancerous and non-cancerous tissues, p16 promoter CpG islands hypermethylation occurred 65%, 60% and 35%, while p15 promoter CpG islands hypermethylation occurred 50%, 40% and 25%. Of 12 HCCs with lower p16 mRNA expression level, 11 cases showed p16 promoter CpG islands methylation (91.6%). Hundred percent (10/10) HCCs with lower p15 mRNA expression level showed p15 promoter CpG islands methylation. Significant correlation between 5'CpG islands methylation and p16/p15 mRNA expression suppression was found. The decreased expression of p16/p15 mRNA or methylation of p16/p15 promoters 5'CpG island was significantly correlate with poor differentiation of HCC (P=0.0083, 0.0102, 0.00271, 0.0218, respectively, P<0.05).
CONCLUSION
p16 and p15 genes transcriptional inactivation might play an important role in hepatocarcinogenesis. 5'CpG islands methylation might be the major mechanism of p16 and p15 genes inactivation in primary HCC in the studied population. 5'CpG islands methylation of p16 and p15 genes might be an early event in hepatocarcinogenesis.
目的
研究p16和p15基因转录抑制及其基因5'CpG岛高甲基化在人类肝细胞癌发生过程中的意义。
方法
采用半定量Northern印迹法检测20例肝细胞癌患者癌组织、癌旁组织及正常肝组织，以及3例因意外死亡的健康成年人的正常肝组织中p16和p15基因的mRNA表达水平。同时用甲基化特异性PCR检测其甲基化状态。
结果
60%（12/20）的肝细胞癌患者癌组织中p16 mRNA表达水平降低，其中2例未检测到p16 mRNA，5例（25%）呈现癌组织<癌旁组织<正常肝组织的变化顺序。50%（10/20）的肝细胞癌患者癌组织中p15 mRNA表达水平降低，其中1例未检测到p15 mRNA，4例（20%）呈现癌组织<癌旁组织<正常肝组织的变化顺序。在癌组织、癌旁组织和正常肝组织中，p16启动子CpG岛高甲基化发生率分别为65%、60%和35%，而p15启动子CpG岛高甲基化发生率分别为50%、40%和25%。在12例p16 mRNA表达水平较低的肝细胞癌中，11例（91.6%）显示p16启动子CpG岛甲基化。100%（10/10）p15 mRNA表达水平较低的肝细胞癌显示p15启动子CpG岛甲基化。发现5'CpG岛甲基化与p16/p15 mRNA表达抑制之间存在显著相关性。p16/p15 mRNA表达降低或p16/p15启动子5'CpG岛甲基化与肝细胞癌低分化显著相关（P分别为0.0083、0.0102、0.00271、0.0218，P<0.05）。
结论
p16和p15基因转录失活可能在肝癌发生中起重要作用。5'CpG岛甲基化可能是所研究人群原发性肝癌中p16和p15基因失活的主要机制。p16和p15基因的5'CpG岛甲基化可能是肝癌发生的早期事件。
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