Botezatu Anca, Bleotu Coralia, Nastase Anca, Anton Gabriela, Bacalbasa Nicolae, Duda Dan, Dima Simona Olimpia, Popescu Irinel
Viral Genetic Engineering Laboratory, Romanian Academy "Stefan S. Nicolau"Virology Institute, Bucharest, Romania.
Antiviral Therapy Engineering Laboratory, Romanian Academy "Stefan S. Nicolau" Virology Institute, Bucharest, Romania.
Cancer Genomics Proteomics. 2015 Jan-Feb;12(1):21-30.
BACKGROUND/AIM: Although pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for therapy, biomarkers for early detection are lacking. Epigenetic silencing of tumor suppressor genes is a majorcontributor to neoplastic transformation. The aim of this study was to identify new factors involved in PDAC progression. The GNMT gene possesses CpG islands in the promoter region and is important in methyl-group metabolism and in maintaining a normal methylation status of the genome.
To test the hypothesis whether GNMT is epigenetically regulated in PDAC, we evaluated the GNMT gene expression and promoter methylation status in 30 paired samples of PDAC and normal pancreatic tissue.
We found significantly higher methylation frequencies (p<0.001) in PDACs (2.82-100%; median, 36.05%) than in controls (0.28-14.02%; median, 4.39%). The GNMT gene expression was decreased in PDACs compared to normal pancreatic tissues in 26/30 cases (86.67%). Furthermore, we showed that treatment with 5-aza-2-deoxycytidine (5-aza-dC) increased GNMT mRNA expression and decreased viability in PDAC cells.
Collectively, these data indicate that GNMT is aberrantly methylated in PDAC representing, thus, a potential major mechanism for gene silencing. Methylation of GNMT gene is directly correlated with disease stage and with tumor grade indicating that these epigenetic effects may be important regulators of PDAC progression.
背景/目的：尽管胰腺导管腺癌（PDAC）仍然是治疗的一大挑战，但缺乏早期检测的生物标志物。肿瘤抑制基因的表观遗传沉默是肿瘤转化的主要促成因素。本研究的目的是确定参与PDAC进展的新因素。GNMT基因在启动子区域拥有CpG岛，在甲基代谢和维持基因组的正常甲基化状态方面很重要。
为了检验GNMT在PDAC中是否受到表观遗传调控的假设，我们评估了30对PDAC和正常胰腺组织样本中GNMT基因的表达和启动子甲基化状态。
我们发现，PDAC中的甲基化频率（p<0.001）显著高于对照组，分别为2.82%-100%（中位数为36.05%）和0.28%-14.02%（中位数为4.39%）。在30例中的26例（86.67%）中，与正常胰腺组织相比，PDAC中的GNMT基因表达降低。此外，我们表明，用5-氮杂-2'-脱氧胞苷（5-aza-dC）处理可增加PDAC细胞中GNMT mRNA的表达并降低其活力。
总体而言，这些数据表明GNMT在PDAC中发生异常甲基化，因此是基因沉默的潜在主要机制。GNMT基因的甲基化与疾病分期和肿瘤分级直接相关，表明这些表观遗传效应可能是PDAC进展的重要调节因子。
