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-β receptor type II (TGFBR2), an important mediator of TGF-β 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.

中文翻译：

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食管鳞状细胞癌的恶性转化涉及II型TGF-β受体的甲基化沉默。

背景技术尽管已经进行了大量研究以研究食管鳞状细胞癌（ESCC）致癌的机制，但仍缺乏对上皮异常增生恶性转化过程中分子变化的了解，尤其是在表观遗传学变化方面。结果为了更好地表征上皮异型增生恶性转化过程中的甲基化变化，对来自食管鳞状细胞癌（ESCC）患者的一系列肿瘤，发育不良和非肿瘤上皮组织样品进行了全基因组亚硫酸氢盐测序分析。鉴定了II型TGF-β受体（TGFBR2）的启动子高甲基化，TGF-β信号传导的重要介体。进一步，我们通过癌症基因组图谱多平台数据以及免疫组化评估了肿瘤样品中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。慢病毒介导TGFBR2的过表达通过诱导细胞周期G2 / M停滞而抑制ESCC细胞系的增殖。此外，TGFBR2的过表达在体内明显抑制了肿瘤的生长。