Dachrut Somkid, Banthaisong S, Sripa M, Paeyao A, Ho C, Lee S A, Kosinski C, Patil M A, Zhang J, Chen X, Sripa Banchob, Pairojkul Chawalit
Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Asian Pac J Cancer Prev. 2009 Oct-Dec;10(4):575-82.
Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene, localized on 1p36, involved in TGF-beta-Smads signaling. To assess its role in liver fluke-associated intrahepatic cholangiocarcinoma (ICC), the promoter methylation status was investigated in 53 ICCs by methylation-specific PCR, with determination of loss of 1p36.1 by microarray comparative genomic hybridization and RUNX3 protein expression by immunohistochemistry. Loss at 1p36.1 was found 41.5% of ICCs (22/53). In addition, DNA hypermethylation of the RUNX3 promoter was found in 49.1% (26/53) of cancers and 57.1% (4/7) of ICC cell lines. The protein was highly expressed in normal bile ducts but mostly decreased in ICCs, 67.9% (n= 36) being negative for immunohistochemical staining. Promoter hypermethylation of RUNX3 was associated with reversible decrease or absence of RUNX3 protein expression (p<0.001), but this was not found to differ with the ICC subtype. In contrast, loss of 1p36.1 demonstrated a significant link (p= 0.020). In conclusion, RUNX3 promoter hypermethylation and loss of 1p36.1 are causal mechanisms for loss of RUNX3 function in liver fluke-associated ICC carcinogenesis.
runt相关转录因子3（RUNX3）是一种候选肿瘤抑制基因，定位于1p36，参与转化生长因子-β-Smads信号传导。为评估其在肝吸虫相关肝内胆管癌（ICC）中的作用，通过甲基化特异性PCR对53例ICC进行启动子甲基化状态研究，通过微阵列比较基因组杂交确定1p36.1缺失，并通过免疫组织化学检测RUNX3蛋白表达。在41.5%（22/53）的ICC中发现1p36.1缺失。此外，在49.1%（26/53）的癌症和57.1%（4/7）的ICC细胞系中发现RUNX3启动子DNA高甲基化。该蛋白在正常胆管中高表达，但在ICC中大多降低，67.9%（n = 36）免疫组织化学染色呈阴性。RUNX3启动子高甲基化与RUNX3蛋白表达可逆性降低或缺失相关（p<0.001），但未发现其在ICC亚型间存在差异。相比之下，1p36.1缺失显示出显著关联（p = 0.020）。总之，RUNX3启动子高甲基化和1p36.1缺失是肝吸虫相关ICC致癌过程中RUNX3功能丧失的因果机制。
