Progressive silencing of p14ARF in oesophageal adenocarcinoma.
Progressive silencing of p14ARF in oesophageal adenocarcinoma.
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DOI：
10.1111/j.1582-4934.2008.00336.x
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发表时间：
2009-02
影响因子：
5.3
通讯作者：
Gjerset RA
中科院分区：
文献类型：
--
作者：
Huang Y;Peters CJ;Fitzgerald RC;Gjerset RA
在西方国家，食管腺癌的发生率正在增加，原因不明，并与癌前病变Barrett食管的相应增加相关，这使腺癌的风险增加了约40至125倍。我们已经研究了疾病进展如何与p14 ARF（ARF）肿瘤抑制因子表达的变化相关，p53肿瘤抑制因子途径的关键调节因子在大约30%的癌症中沉默，但在食管癌中的作用尚不清楚。本研究采用定量PCR、RT-PCR、甲基化特异性PCR和染色质免疫沉淀技术，对食管腺癌组织标本和细胞系中ARF的调控和功能进行了研究。我们发现在从正常食管上皮到Barrett食管再到腺癌的疾病进展过程中，ARF表达显著降低（P< 0.001），其中57/76（75%）腺癌显示ARF表达水平检测不到。腺癌中ARF表达的保留是生存率增加的一个非常重要的指标（P< 0.001），并且在多变量模型中优于所有临床变量。CpG甲基化以及组蛋白H3的赖氨酸9和27甲基化独立地导致腺癌细胞系中ARF基因的沉默，并且可以被5-氮杂-2 ′-脱氧胞苷逆转。结果表明，ARF基因沉默参与了食管腺癌的发病机制，并表明DNA或组蛋白甲基化可以提供ARF基因沉默的主要机制。ARF基因沉默可能是一个有用的标志物，用于评估疾病进展风险和不良预后。
The frequency of oesophageal adenocarcinoma is increasing in Western countries for unknown reasons, and correlates with a corresponding increase in the pre-malignant condition, Barrett's Oesophagus, which raises the risk of adenocarcinoma by some 40- to 125-fold. We have examined how disease progression correlates with changes in expression of the p14ARF (ARF) tumour suppressor, a key regulator of the p53 tumour suppressor pathway that is silenced in some 30% of cancers overall, but for which a role in oesophageal cancer is unclear. We have used quantitative PCR, RT-PCR, methylation-specific PCR and chromatin-immunoprecipitation to examine the regulation and function of ARF in oesophageal adenocarcinoma tissue specimens and cell lines. We find highly significant reductions (P< 0.001) in ARF expression during disease progression from normal oesophageal epithelium to Barrett's Oesophagus to adenocarcinoma, with 57/76 (75%) adenocarcinomas displaying undetectable levels of ARF expression. Retention of ARF expression in adenocarcinoma is a highly significant indicator of increased survival (P< 0.001) and outperforms all clinical variables in a multivariate model. CpG methylation as well as histone H3 methylation of lysines 9 and 27 contribute independently to ARF gene silencing in adenocarcinoma cell lines and can be reversed by 5-aza-2′-deoxycytidine. The results suggest that silencing of ARF is involved in the pathogenesis of oesophageal adenocarcinoma and show that either DNA or histone methylation can provide the primary mechanism for ARF gene silencing. Silencing of ARF could provide a useful marker for increased risk of progression and poor prognosis.
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影响因子：
8.8
作者：
Rockett JC;Larkin K;Darnton SJ;Morris AG;Matthews HR
通讯作者：
Matthews HR
DOI：
10.1046/j.1440-1746.2003.03048.x
发表时间：
2003-06-01
影响因子：
4.1
作者：
Dolan, K;Morris, AI;Sutton, R
通讯作者：
Sutton, R
DOI：
10.1016/j.biocel.2006.02.008
发表时间：
2006-01-01
影响因子：
4
作者：
Gallagher, Stuart J.;Kefford, Richard F.;Rizos, Helen
通讯作者：
Rizos, Helen
影响因子：
6.4
作者：
Polednak, AP
通讯作者：
Polednak, AP
影响因子：
11.2
作者：
Clément, G;Bosman, FT;Benhattar, J
通讯作者：
Benhattar, J