Hypermethylated MAL gene - a silent marker of early colon tumorigenesis.
Hypermethylated MAL gene - a silent marker of early colon tumorigenesis.
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DOI：
10.1186/1479-5876-6-13
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发表时间：
2008-03-17
影响因子：
7.4
通讯作者：
Lothe RA
中科院分区：
文献类型：
--
作者：
Lind GE;Ahlquist T;Kolberg M;Berg M;Eknaes M;Alonso MA;Kallioniemi A;Meling GI;Skotheim RI;Rognum TO;Thiis-Evensen E;Lothe RA
肿瘤来源的异常甲基化DNA可能作为癌症的诊断生物标志物，但到目前为止，很少有这样的标志物已被确定。本研究的目的是探讨MAL（T细胞分化蛋白）基因作为结直肠肿瘤早期表观遗传学诊断标志物的潜力。采用甲基化特异性聚合酶链反应（MSP）分析了218个样本中MAL启动子甲基化状态，包括正常粘膜（n = 44）、结直肠腺瘤（n = 63）、癌（n = 65）和各种癌细胞系（n = 46）。进行直接亚硫酸氢盐测序以确认MSP结果。采用真实的时间定量分析法研究表观遗传药物治疗前后MAL基因的表达。MAL的免疫组织化学分析使用正常结肠粘膜样品（n = 5）和292个结直肠肿瘤的组织微阵列。亚硫酸氢盐测序显示甲基化在MAL启动子内分布不均匀，MSP分析显示，在大多数结直肠癌（49/61，80%）和腺瘤（45/63，71%）中，靠近转录起始点的区域被高甲基化。与此相反，只有少数正常粘膜样本显示高甲基化（1/23，4%）。在体外模型中，MAL的高甲基化与基因表达的减少或丢失显著相关。此外，去除甲基化重新诱导结肠癌细胞系中的基因表达。MAL蛋白在正常结肠粘膜上皮细胞中表达，而在同类型的结肠癌细胞中不表达。MAL基因启动子甲基化存在于绝大多数良性和恶性结直肠肿瘤中，而在正常粘膜中很少，这使得它适合作为结直肠肿瘤发生的早期诊断标志物。
Tumor-derived aberrantly methylated DNA might serve as diagnostic biomarkers for cancer, but so far, few such markers have been identified. The aim of the present study was to investigate the potential of the MAL (T-cell differentiation protein) gene as an early epigenetic diagnostic marker for colorectal tumors. Using methylation-specific polymerase chain reaction (MSP) the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44), colorectal adenomas (n = 63), carcinomas (n = 65), and various cancer cell lines (n = 46). Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5) and a tissue microarray with 292 colorectal tumors. Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80%) as well as in adenomas (45/63, 71%). In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%). The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type. Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.
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影响因子：
8.8
作者：
Deng, G;Peng, E;Gum, J;Terdiman, J;Sleisenger, M;Kim, Y S
通讯作者：
Kim, Y S
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
DOI：
10.1073/pnas.84.7.1997
发表时间：
1987-04-01
影响因子：
11.1
作者：
ALONSO, MA;WEISSMAN, SM
通讯作者：
WEISSMAN, SM
影响因子：
82.9
作者：
Kononen, J;Bubendorf, L;Kallioniemi, OP
通讯作者：
Kallioniemi, OP
影响因子：
8.8
作者：
Meling, G I;Lothe, R A;Borresen, A L;Hauge, S;Graue, C;Clausen, O P;Rognum, T O
通讯作者：
Rognum, T O