Choi Chel Hun, Lee Kyung-Mee, Choi Jung-Joo, Kim Tae-Joong, Kim Woo Young, Lee Jeong-Won, Lee Sun-Joo, Lee Je-Ho, Bae Duk-Soo, Kim Byoung-Gie
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Cancer Lett. 2007 Sep 18;255(1):26-33. doi: 10.1016/j.canlet.2007.03.015. Epub 2007 Apr 30.
We examined the promoter methylation status and LOH of the chromosome 3p genes, von Hippel-Lindau disease (VHL), retinoic acid receptor beta (RAR-beta), RAS association domain family 1A (RASSF1A), and fragile histidine triad (FHIT), in 37 samples of cervical squamous cell carcinoma and corresponding noncancerous tissues. We also analyzed the expression of RAR-beta protein by immunohistochemistry. Promoter hypermethylation in RAR-beta and FHIT was detected in 41% and 24% of tumors, respectively, whereas, no hypermethylation was detected in the corresponding noncancerous tissues. LOH in the regions of VHL, RAR-beta, RASSF1A, and FHIT was observed in 3%, 30%, 22%, and 10% of informative cases, respectively. There were no correlations between LOH and promoter hypermethylation for all of these genes. Absent immunostaining of RAR-beta protein correlated with hypermethylation and/or LOH of RAR-beta gene. In addition, it correlated with higher level of SCC antigen and more frequent lymph node metastasis. Although biallelic inactivation by hypermethylation and concomitant LOH was infrequent, the high frequency of promoter hypermethylation and/or LOH of RAR-beta and FHIT suggest that they play a role in cervical carcinogenesis independently. In addition, expression of RAR-beta protein might be used as a prognostic factor in this disease.
我们检测了37例宫颈鳞状细胞癌样本及相应癌旁组织中3号染色体上的抑癌基因，包括希佩尔-林道病（VHL）、维甲酸受体β（RAR-β）、RAS关联结构域家族1A（RASSF1A）和脆性组氨酸三联体（FHIT）的启动子甲基化状态及杂合性缺失（LOH）情况。我们还通过免疫组化分析了RAR-β蛋白的表达。RAR-β和FHIT启动子高甲基化在肿瘤中的检出率分别为41%和24%，而在相应癌旁组织中未检测到高甲基化。VHL、RAR-β、RASSF1A和FHIT区域的LOH在信息可分析病例中的检出率分别为3%、30%、22%和10%。所有这些基因的LOH与启动子高甲基化之间均无相关性。RAR-β蛋白免疫染色缺失与RAR-β基因的高甲基化和/或LOH相关。此外，它还与较高水平的鳞状细胞癌抗原及更频繁的淋巴结转移相关。尽管高甲基化伴随LOH导致的双等位基因失活并不常见，但RAR-β和FHIT启动子高甲基化和/或LOH的高频率表明它们在宫颈癌发生中各自发挥作用。此外，RAR-β蛋白的表达可能作为该疾病的一个预后因素。
