Panagopoulou Maria, Fanidis Dionysios, Aidinis Vassilis, Chatzaki Ekaterini
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, GR-68100 Alexandroupolis, Greece.
Biomedical Sciences Research Center Alexander Fleming, Institute of Bio-Innovation, GR-16672 Athens, Greece.
Int J Mol Sci. 2021 Nov 4;22(21):11958. doi: 10.3390/ijms222111958.
Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 () is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, methylation profiles in health and malignancy are not described. We examined in silico the methylation of analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected -value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of in health and cancer and points out specific DMCs of value as prognostic biomarkers.
由胞外核苷酸焦磷酸酶/磷酸二酯酶2（ENPP2）编码的自分泌运动因子（ATX）是参与癌症的溶血磷脂酸（LPA）合成中的关键酶。尽管已经报道了其异常表达，但尚未描述其在健康和恶性肿瘤中的甲基化谱。我们通过分析公开可用的甲基化组数据集，在计算机上检查了ENPP2的甲基化，以识别差异甲基化的CpG（DMC），然后将其与基因和异构体水平的表达相关联。显著性指标设定为FDR校正后的P值<0.05。健康组织在所有基因体CG中呈现甲基化，而在启动子相关（PA）区域中水平较低，而在大多数检查的肿瘤（肝癌、黑色素瘤、结直肠癌、肺癌和前列腺癌）中甲基化模式则相反。在启动子中鉴定出的DMC位于多个转录因子识别的位点，表明其参与基因表达。甲基化改变与癌细胞系中的侵袭性表型相关。在前列腺癌和肺腺癌中，PA CG甲基化增加与ENPP2 mRNA表达降低和不良预后参数相关。总体而言，我们的结果证实甲基化是癌症中ATX表达调控的一个活跃水平。我们的研究提供了ENPP2在健康和癌症中的甲基化状态的扩展描述，并指出了作为预后生物标志物有价值的特定DMC。
