HOXA10 启动子的甲基化指导 miR-196b-5p 依赖的胃癌细胞增殖和侵袭。
Methylation of the HOXA10 Promoter Directs miR-196b-5p-Dependent Cell Proliferation and Invasion of Gastric Cancer Cells.
机构信息
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida.
出版信息
Mol Cancer Res. 2018 Apr;16(4):696-706. doi: 10.1158/1541-7786.MCR-17-0655. Epub 2018 Feb 16.
The cross-talk between epigenetics and miRNA expression plays an important role in human tumorigenesis. Herein, the regulation and role of miR-196b-5p in gastric cancer was investigated. qRT-PCR demonstrated that miR-196b-5p is significantly overexpressed in human gastric cancer tissues ( < 0.01). In addition, it was determined that HOXA10, a homeobox family member and host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels ( < 0.001). Quantitative pyrosequencing methylation analysis demonstrated significantly lower levels of DNA methylation at the HOXA10 promoter in gastric cancer, as compared with nonneoplastic gastric mucosa specimens. 5-Aza-2'-deoxycytidine treatment confirmed that demethylation of HOXA10 promoter induces the expression of HOXA10 and miR-196b-5p in gastric cancer cell model systems. Using the Tff1 knockout mouse model of gastric neoplasia, hypomethylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared with normal gastric mucosa from Tff1 wild-type mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells led to an increased HOXA10 promoter methylation with reduced expression of HOXA10 and miR-196b-5p. Functionally, miR-196b-5p reconstitution promoted human gastric cancer cell proliferation and invasion In summary, the current data demonstrate overexpression of miR-196b-5p in gastric cancer and suggest that TFF1 plays an important role in suppressing the expression of miR-196b-5p by mediating DNA methylation of the HOXA10 promoter. Loss of TFF1 expression may promote proliferation and invasion of gastric cancer cells through induction of promoter hypomethylation and expression of the HOXA10/miR-196b-5p axis. This study indicates that loss of TFF1 promotes the aberrant overexpression of HOXA10 and miR-196b-5p by demethylation of the HOXA10 promoter, which provides a new perspective of TFF1/HOXA10/miR-196b-5p functions in human gastric cancer. .
表观遗传学和 miRNA 表达的串扰在人类肿瘤发生中发挥重要作用。本文研究了 miR-196b-5p 在胃癌中的调控和作用。qRT-PCR 显示 miR-196b-5p 在人胃癌组织中显著过表达（<0.01）。此外，确定同源盒家族成员 HOXA10 和 miR-196b-5p 的宿主基因，过表达并与 miR-196b-5p 表达水平呈正相关（<0.001）。定量焦磷酸测序甲基化分析显示，与非肿瘤性胃黏膜标本相比，胃癌中 HOXA10 启动子的 DNA 甲基化水平显著降低。5-Aza-2'-脱氧胞苷处理证实，HOXA10 启动子的去甲基化诱导胃癌细胞模型系统中 HOXA10 和 miR-196b-5p 的表达。使用 Tff1 敲除小鼠胃癌模型，与 Tff1 野生型小鼠的正常胃黏膜相比，在胃肿瘤中观察到 HOXA10 和 miR-196b-5p 的低甲基化和过表达。在机制上，TFF1 在人胃癌细胞中的重建导致 HOXA10 启动子甲基化增加，HOXA10 和 miR-196b-5p 的表达减少。功能上，miR-196b-5p 的重建促进了人胃癌细胞的增殖和侵袭。总之，本研究表明 miR-196b-5p 在胃癌中过表达，并提示 TFF1 通过介导 HOXA10 启动子的 DNA 甲基化在抑制 miR-196b-5p 的表达中发挥重要作用。TFF1 表达的缺失可能通过诱导启动子低甲基化和 HOXA10/miR-196b-5p 轴的表达促进胃癌细胞的增殖和侵袭。本研究表明，TFF1 的缺失通过 HOXA10 启动子的去甲基化促进 HOXA10 和 miR-196b-5p 的异常过表达，为 TFF1/HOXA10/miR-196b-5p 在人类胃癌中的功能提供了一个新的视角。
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