Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
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DOI：
10.1002/ijc.25086
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发表时间：
2010-08-01
影响因子：
6.4
通讯作者：
Barany, Francis
中科院分区：
文献类型：
--
作者：
Cheng, Yu-Wei;Idrees, Kamran;Shattock, Richard;Khan, Sajid A.;Zeng, Zhaoshi;Brennan, Cameron W.;Paty, Philip;Barany, Francis
IGF2的印迹缺失（LOI）在许多癌症中是一种常见的事件，通常会激活母体沉默的等位基因。由此产生的双等位基因IGF2表达与其启动子附近差异甲基化区域（DMR）的低甲基化密切相关。研究还表明，IGF2在人类恶性肿瘤中过度表达；然而，这种现象及其与异常DMR甲基化的联系尚未在结直肠癌（CRC）中报道。本研究的目的是确定CRC中IGF2 LOI、过表达和DMR低甲基化之间的关系。通过分析97例原发性结直肠癌和64例匹配的正常结直肠组织中IGF2和H19的甲基化，我们发现IGF2 LOI与IGF2和H19的DMR低甲基化之间存在显著相关性。此外，在167例原发性结直肠癌肿瘤和32例正常组织的Affymetrix表达数据分析中，15%的肿瘤显示IGF2显著升高。我们进一步研究了IGF2水平的显著升高是否与IGF2或H19低甲基化有关，但没有发现显著相关性。然而，我们证明了明显的IGF2过表达，而不是LOI，与CRC微卫星不稳定性负相关。这些观察结果表明，IGF2的表达，特别是当转录水平显著升高时，是与LOI无关的机制的结果。我们的研究结果表明，IGF2通过两种不同形式的异常基因表达参与结直肠癌的肿瘤发生。
Loss of imprinting (LOI) of IGF2 is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation has not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumor and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through two different forms of aberrant gene expression.
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影响因子：
30.8
作者：
MOULTON, T;CRENSHAW, T;TYCKO, B
通讯作者：
TYCKO, B
影响因子：
64.8
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Hark, AT;Schoenherr, CJ;Tilghman, SM
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Tilghman, SM
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作者：
Cui, HM;Cruz-Correa, M;Feinberg, AP
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Feinberg, AP
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作者：
Cui, HM;Horon, IL;Feinberg, AP
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Feinberg, AP
影响因子：
64.8
作者：
Bell, AC;Felsenfeld, G
通讯作者：
Felsenfeld, G