Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, 510632, China.
Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Department of Gastrointestinal Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
Cancer Lett. 2022 Feb 1;526:322-334. doi: 10.1016/j.canlet.2021.11.006. Epub 2021 Nov 9.
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.
miRNA（miRNA）与宿主长链非编码 RNA（lncRNA）之间的关系尚不清楚。在这里，胃癌（GC）中miRNA-210（miR-210）和宿主 lncRNA MIR210HG 的表达水平显著增加且呈正相关。增益和功能丧失研究表明，miR-210 和 MIR210HG 协同促进 GC 细胞在体外的迁移和侵袭。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 DEAH -box 解旋酶 9（DHX9）相互作用，增加 DHX9/c-Jun 复合物在基质金属蛋白酶（MMPs）启动子上的占有率，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 网络转录抑制剂（MNT）的表达，从而增强迁移和侵袭。最后，原癌基因 MYC（c-Myc）反式激活 miR-210 和 MIR210HG。miR-210 或/和 MIR210HG 的过表达可以挽救沉默 c-Myc 对迁移和侵袭的抑制作用。此外，c-Myc 抑制剂显著降低了 GC 体内肺转移的发生率。总之，我们的研究结果确定了一种新的机制，即 c-Myc 激活的 miR-210 和 MIR210HG 协同促进 GC 的转移。
