Shanghai Putuo District People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China.
School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China.
J Cell Mol Med. 2020 Mar;24(5):2772-2790. doi: 10.1111/jcmm.15030. Epub 2020 Feb 6.
Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24-2 and Pim1 are up-regulated in human liver cancers, and miR24-2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24-2 increases the expression of N6-adenosine-methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri-methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24-2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24-2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24-2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24-2 in liver cancer. This study elucidates a novel mechanism for miR24-2 in liver cancer and suggests that miR24-2 may be used as novel therapeutic targets of liver cancer.
几种 microRNA 与癌症发生和肿瘤进展有关。在此，我们的观察结果表明，miR24-2 和 Pim1 在人肝癌中均上调，miR24-2 可加速肝癌细胞在体外和体内的生长。从机制上讲，miR24-2 增加了 N6-腺苷甲基转移酶 METTL3 的表达，进而通过 RNA 甲基化修饰促进了 miR6079 的表达。此外，miR6079 靶向 JMJD2A，然后增加了第九个赖氨酸（H3K9me3）上组蛋白 H3 的三甲基化。因此，miR24-2 通过增加 miR6079 抑制 JMJD2A，从而增加 H3K9me3。引人注目的是，miR24-2 增加了依赖于 H3K9me3 和 METTL3 的 Pim1 的表达。值得注意的是，我们的研究结果表明，miR24-2 通过 Pim1 激活改变了几个相关基因（pHistone H3、SUZ12、SUV39H1、Nanog、MEKK4、pTyr）并加速了肝癌细胞的进展。特别是，Pim1 是 miR24-2 在肝癌中的致癌作用所必需的。本研究阐明了 miR24-2 在肝癌中的新机制，并表明 miR24-2 可能成为肝癌的新治疗靶点。
