OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.
OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.
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DOI：
10.1371/journal.pone.0002990
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发表时间：
2008-08-20
期刊：
影响因子：
3.7
通讯作者：
Tao Q
中科院分区：
文献类型：
--
作者：
Cui Y;Ying Y;van Hasselt A;Ng KM;Yu J;Zhang Q;Jin J;Liu D;Rhim JS;Rha SY;Loyo M;Chan AT;Srivastava G;Tsao GS;Sellar GC;Sung JJ;Sidransky D;Tao Q
CpG甲基化沉默肿瘤抑制基因(TSG)的发现揭示了肿瘤发生的分子机制和潜在的肿瘤生物标志物。11q25杂合性缺失在包括鼻咽癌在内的多种肿瘤中很常见。OPCML位于11q25，是我们通过数字表达消减发现的下调基因之一。半定量RT-PCR显示OPCML在鼻咽癌和其他常见肿瘤中频繁沉默，多重差异DNA-PCR未检测到纯合子缺失。相反，OPCML启动子甲基化在多种肿瘤细胞系(鼻咽、食道、肺、胃、结肠、肝、乳腺、宫颈、前列腺癌)、淋巴瘤细胞系(非霍奇金和霍奇金淋巴瘤、鼻NK/T细胞淋巴瘤)和原发肿瘤中频繁检测到，但在任何非肿瘤细胞系中均未检测到，在正常上皮组织中很少弱甲基化。药物和基因去甲基化恢复了OPCML的表达，表明直接的表观遗传沉默。我们进一步发现，OPCML是应激反应的，但当它的启动子甲基化时，这种反应会受到表观遗传的损害。通过内源性沉默，OPCML的异位表达显著抑制了癌细胞的锚定依赖性和非依赖性生长。因此，通过功能表观遗传学，我们确定OPCML是一种广泛的肿瘤抑制因子，在多种恶性肿瘤中经常被甲基化失活。
Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing. Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.
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DOI：
10.1073/pnas.0700153104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Jin, Hongchuan;Wang, Xian;Tao, Qian
通讯作者：
Tao, Qian
影响因子：
20.3
作者：
Srivastava, G;Wong, KY;Tao, Q
通讯作者：
Tao, Q
影响因子：
4.7
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
3.5
作者：
Eagleson, KL;Pimenta, AF;Levitt, P
通讯作者：
Levitt, P
影响因子：
8
作者：
Deng, W;Tsao, SW;Cheung, ALM
通讯作者：
Cheung, ALM