miR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells.
miR-639 Expression Is Silenced by DNMT3A-Mediated Hypermethylation and Functions as a Tumor Suppressor in Liver Cancer Cells.
复制标题
DOI：
10.1016/j.ymthe.2019.11.021
复制
发表时间：
2019-11
期刊：
影响因子：
--
通讯作者：
Jingshui Xiao;Yankun Liu;Fuxia Wu;Ruiyan Liu;Yongli Xie;Qian Yang;Yu-Feng Li;Min Liu;Sheng-ping Li;Hua Tang
中科院分区：
文献类型：
--
作者：
Jingshui Xiao;Yankun Liu;Fuxia Wu;Ruiyan Liu;Yongli Xie;Qian Yang;Yu-Feng Li;Min Liu;Sheng-ping Li;Hua Tang
新出现的证据表明，DNA甲基化异常有助于肝癌的发生。然而，监管机制尚不清楚。在这里，我们发现microRNA-639 （miR-639）在肝癌组织和细胞中的表达下调。miR-639表达的抑制归因于其启动子区域的高甲基化，而DNA甲基转移酶（DNMT3A）被发现介导这种高甲基化。抑制miR-639的表达促进了体外细胞生长和迁移/侵袭以及异种移植小鼠模型中肿瘤的生长。此外，miR-639结合MYST2和ZEB1的30 UTR并抑制它们的表达。MYST2促进肝癌细胞生长，ZEB1促进肝癌细胞迁移/侵袭。MYST2和ZEB1的异位表达抵消了miR-639诱导的恶性肿瘤抑制，这与miR-639与MYST2和ZEB1在临床肝细胞癌（HCC）组织中的表达呈负相关一致。因此，dnmt3a介导的高甲基化抑制了miR-639的表达，降低了MSYT2和ZEB1的表达，从而促进了肝癌的发生。这些发现可能揭示肝癌恶性过程中mirna异常表达的机制，并为肝癌提供新的生物标志物。
Emerging evidence has indicated that abnormal methylation of DNA contributes to hepatocarcinogenesis. However, the regulatory mechanisms are not well known. Here, we revealed that microRNA-639 (miR-639) expression is downregulated in liver cancer tissues and cells. The repression of miR-639 expression was attributed to hypermethylation in its promoter region, and DNA methyltransferase (DNMT3A) was found to mediate this hypermethylation. Repression of miR-639 expression promoted cell growth and migration/invasion in vitro and the growth of tumors in xenograft mouse models. Furthermore, miR-639 bound to the 3 0 UTR of both MYST2 and ZEB1 and suppressed their expression. MYST2 promoted the growth of liver cancer cells and ZEB1 facilitated the migration/invasion of liver cancer cells. Ectopic expression of MYST2 and ZEB1 counteracted the repression of malignancy induced by miR-639, which coincided with the reciprocal correlation between miR-639 and MYST2 and ZEB1 expression in clinical hepatocellular carcinoma (HCC) tissues. Thus, DNMT3A-mediated hypermethylation suppressed miR-639 expression, derepressing the expression of MSYT2 and ZEB1, which promoted tumorigenesis of liver cancer. These findings may shed light on the mechanism of abnormal expression of miRNAs involved in the malignancy of liver cancer and provide new biomarkers for liver cancer.