Hypermethylation of PGCP gene is associated with human bronchial epithelial cells immortalization
Hypermethylation of PGCP gene is associated with human bronchial epithelial cells immortalization
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PGCP基因高甲基化与人支气管上皮细胞永生化相关
DOI：
10.1016/j.gene.2017.11.063
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发表时间：
2018-02-05
期刊：
影响因子：
3.5
通讯作者：
Li, Daochuan
中科院分区：
文献类型：
--
作者：
Gao, Chen;Xing, Xiumei;Li, Daochuan
细胞永生化是癌症发展的第一步。为了鉴定人原代支气管上皮细胞（HPBEC）永生化过程中受DNA甲基化调节的差异表达基因，通过将SV40 LT和人端粒酶逆转录酶（hTERT）的催化亚基引入HPBEC中产生永生化HBE细胞系（HBETT）。通过 mRNA 和 DNA 甲基化微阵列比较这两种细胞的转录组和 DNA 甲基化组。 mRNA 微阵列的结果揭示了许多基因的表达在细胞永生化时发生变化。我们确定的特征包括整体低甲基化、ECM-受体相互作用的扰动、粘着斑以及与细胞永生化相关的 PI3K-Akt 通路。此外，我们还揭示了 42 个基因的 CpG 岛 (CGI) 内的 155 个分化甲基化区域 (DMR)，以及可能参与 HBE 细胞永生化的几个关键途径的扰动。其中，血浆谷氨酸羧肽酶（PGCP）基因的高甲基化特异地出现在肺癌组织中。在永生化 HBETT 细胞和苯并[a]芘 (Bap) 转化的 HBE 细胞中均观察到启动子高甲基化对 PGCP 表达的抑制。总之，这些发现为表观遗传修饰提供了新的见解，这些修饰对于细胞永生化的转变和维持至关重要。
Cell immortalization is the initial step for cancer development. To identify the differentially expressed genes regulated by DNA methylation over the course of human primary bronchial epithelial cell (HPBECs) immortalization, an immortalized HBE cell line (HBETT) was generated via introduction of an SV40 LT and a catalytic subunit of human telomerase reverse transcriptase (hTERT) into the HPBECs. Microarrays of mRNA and DNA methylation were performed to compare the transcriptomes and DNA methylomes between these two types of cells. The results from the mRNA microarray revealed many genes whose expression changed upon cell immortalization. We identified signatures including global hypomethylation, perturbation of ECM-receptor interaction, focal adhesion, and PI3K-Akt pathways associated with cell immortalization. Moreover, we revealed 155 differentiated methylation regions (DMRs) within the CpG islands (CGIs) of 42 genes and the perturbation of several key pathways that might be involved in HBE cell immortalization. Among these genes, the hypermethylation of the plasma glutamate carboxypeptidase (PGCP) gene appeared specifically in lung cancer tissues. The inhibition of PGCP expression by promoter hypermethylation was observed in both immortal HBETT cells and benzo[a]pyrene (Bap)-transformed HBE cells. In conclusion, these findings provide new insight into the epigenetic modifications that are critical in the transition and maintenance of cell immortalization.