c-Myc-activated intronic miR-210 and lncRNA MIR210HG synergistically promote the metastasis of gastric cancer
c-Myc-activated intronic miR-210 and lncRNA MIR210HG synergistically promote the metastasis of gastric cancer
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DOI：
10.1016/j.canlet.2021.11.006
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发表时间：
2022-02-01
期刊：
影响因子：
9.7
通讯作者：
Lin, Xue-Jia
中科院分区：
文献类型：
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作者：
Li, Zhi-Yong;Xie, Ying;Lin, Xue-Jia
microRNA (miRNA) 和宿主长非编码 RNA (lncRNA) 之间的关系仍不清楚。在这里，microRNA-210（miR-210）和宿主lncRNA MIR210HG的表达水平在胃癌（GC）中显着增加并呈正相关。功能获得和丧失研究表明，miR-210 和 MIR210HG 协同促进体外 GC 细胞的迁移和侵袭。此外，同时表达miR-210和MIR210HG的GC亚系在体内表现出协同促进肺转移的作用。从机制上讲，MIR210HG 与 DExH-box 解旋酶 9 (DHX9) 相互作用，增加 DHX9/c-Jun 复合物对基质金属肽酶 (MMP) 启动子的占据，从而促进 GC 细胞的迁移和侵袭。此外，miR-210直接抑制多巴胺受体D5（DRD5）、丝氨酸/苏氨酸激酶24（STK24）和MAX网络转录抑制子（MNT）的表达，从而增强迁移和侵袭。最后，MYC 原癌基因 (c-Myc) 反式激活 miR-210 和 MIR210HG。 miR-210或/和MIR210HG的过表达可以通过沉默c-Myc来挽救对迁移和侵袭的抑制作用。此外，c-Myc抑制剂显着降低体内GC的肺转移。总的来说，我们的研究结果确定了一种新机制，c-Myc 激活的 miR-210 和 MIR210HG 通过该机制协同促进 GC 转移。
The relationship between microRNA (miRNA) and hosting long non-coding RNA (lncRNA) remains unclear. Here, the expression levels of microRNA-210 (miR-210) and hosting lncRNA MIR210HG are significantly increased and positively correlated in gastric cancer (GC). Gain-and loss-of-function studies demonstrate that miR-210 and MIR210HG synergistically promote the migration and invasion of GC cells in vitro. Furthermore, GC sublines simultaneously expressing miR-210 and MIR210HG display synergistic promotion of lung metastasis in vivo. Mechanistically, MIR210HG interacts with DExH-box helicase 9 (DHX9) to increase DHX9/c-Jun complex's occupancy on the promoter of matrix metallopeptidases (MMPs), and thus promotes migration and invasion of GC cells. Additionally, miR-210 directly suppresses the expression of dopamine receptor D5 (DRD5), serine/ threonine kinase 24 (STK24) and MAX network transcriptional repressor (MNT), resulting in enhanced migration and invasion. Finally, MYC proto-oncogene (c-Myc) transactivates miR-210 and MIR210HG. Overexpression of miR-210 or/and MIR210HG can rescue the inhibitory effect on the migration and invasion by silencing c-Myc. Moreover, c-Myc inhibitor significantly decreases lung metastasis of GC in vivo. Collectively, our findings identify a novel mechanism, by which c-Myc-activated miR-210 and MIR210HG synergistically promote the metastasis of GC.