Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma
Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma
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TGF-β II型受体甲基化沉默参与食管鳞癌恶变
DOI：
10.1186/s13148-020-0819-6
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发表时间：
2020-02-11
影响因子：
5.7
通讯作者：
Jiao, Yuchen
中科院分区：
文献类型：
--
作者：
Ma, Yarui;He, Siyuan;Jiao, Yuchen
背景尽管已经进行了大量研究来探讨食管鳞状细胞癌（ESCC）的致癌机制，但对上皮不典型增生恶性转化过程中分子改变的了解仍然缺乏，特别是关于表观遗传变化。结果为了更好地表征上皮不典型增生恶性转化过程中的甲基化变化，对食管鳞状细胞癌（ESCC）患者的一系列肿瘤、不典型增生和非肿瘤上皮组织样本进行全基因组亚硫酸氢盐测序分析。 TGF-β II 型受体 (TGFBR2) 是 TGF-β 信号转导的重要介质，其启动子高度甲基化已被鉴定。此外，我们通过癌症基因组图谱多平台数据以及免疫组织化学评估了肿瘤样本中 TGFBR2 的甲基化和表达。此外，用DNA甲基转移酶抑制剂5-Aza-2'-脱氧胞苷处理ESCC细胞系，可重新激活TGFBR2的表达。介导TGFBR2过度表达的慢病毒通过诱导细胞周期G2/M阻滞来抑制ESCC细胞系的增殖。此外，TGFBR2的过表达在体内明显抑制肿瘤生长。结论 ESCC 中 TGFBR2 甲基化沉默的特征将使我们能够进一步探讨这种表观遗传变化是否可以被视为食管上皮不典型增生恶性转化的预测因素，以及使用 TGFBR2 激动剂是否可以为 ESCC 患者带来新的治疗策略。
Background Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes. Results To better characterize the methylation changes during the malignant transformation of epithelial dysplasia, a whole-genome bisulfite sequencing analysis was performed on a series of tumor, dysplastic, and non-neoplastic epithelial tissue samples from esophageal squamous cell carcinoma (ESCC) patients. Promoter hypermethylation in TGF-beta receptor type II (TGFBR2), an important mediator of TGF-beta signaling, was identified. Further, we evaluated the methylation and expression of TGFBR2 in tumor samples through The Cancer Genome Atlas multiplatform data as well as immunohistochemistry. Moreover, treatment of ESCC cell lines with5-Aza-2 '-deoxycytidine, a DNA methyltransferase inhibitor, reactivated the expression of TGFBR2. The lentiviral mediating the overexpression of TGFBR2 inhibited the proliferation of ESCC cell line by inducing cell cycle G2/M arrest. Furthermore, the overexpression of TGFBR2 inhibited the tumor growth obviously in vivo. Conclusions The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.