Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer
Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer
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PTTG1IP启动子高甲基化导致早期非小细胞肺癌低表达
DOI：
10.3892/ol.2019.10400
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发表时间：
2019-08-01
期刊：
影响因子：
2.9
通讯作者：
Jiang，Handong
中科院分区：
文献类型：
--
作者：
Tan，Xiaoming;Zhang，Sufen;Jiang，Handong
尽管临床需要早期诊断，但肺癌的早期事件及其机制尚未完全了解。垂体瘤转化基因1结合因子（PTTG 1 IP）是一种肿瘤相关基因;然而，据我们所知，其与肺癌的相关性尚未报道。本研究分析了PTTG 1 IP在早期非小细胞肺癌（NSCLC）样本中的表达，并研究了其表观遗传调控机制。结果显示，PTTG 1 IP在NSCLC组织中的mRNA水平较癌旁组织显著下调43%。此外，该基因的过表达显著抑制细胞增殖。根据癌症基因组图谱的数据，肺腺癌和肺鳞状细胞癌病例中PTTG 1 IP基因甲基化水平与表达水平之间存在显着负相关性。6对早期NSCLC组织样本的还原代表性亚硫酸氢盐测序（RRBS）分析表明，肺癌组织中PTTG 1 IP启动子的CpG岛海岸是高甲基化的，这通过亚硫酸氢盐扩增子测序在12对早期NSCLC样本中得到进一步验证。在用5-aza-2′-deoxycytidine处理以降低启动子区域的DNA甲基化后，PTTG 1 IP mRNA水平增加，表明PTTG 1 IP启动子DNA甲基化水平负调控PTTG 1 IP转录。结论：在早期NSCLC中，PTTG 1 IP基因受其启动子区DNA甲基化调控，可能参与肺癌的发生发展。
Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood. Pituitary tumor transforming gene 1 binding factor (PTTG1IP) is a tumor-associated gene; however, to the best of our knowledge, its association with lung cancer has not been reported. The present study analyzed PTTG1IP expression in early-stage non-small cell lung cancer (NSCLC) samples and investigated its epigenetic regulatory mechanisms. The results revealed that the mRNA level of PTTG1IP in NSCLC tissues was significantly downregulated by 43% compared with that in adjacent tissues. In addition, overexpression of this gene significantly inhibited cell proliferation. According to data from The Cancer Genome Atlas, a significant negative correlation was identified between the PTTG1IP gene methylation level and expression level in lung adenocarcinoma and lung squamous cell carcinoma cases. Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing. Following treatment with 5-aza-2′-deoxycytidine to reduce DNA methylation in the promoter region, the PTTG1IP mRNA level increased, indicating that the PTTG1IP promoter DNA methylation level negatively regulates PTTG1IP transcription. In conclusion, in early-stage NSCLC, the PTTG1IP gene is regulated by DNA methylation in its promoter region, which may participate in the development and progression of lung cancer.