Research Center for Translational Medicine at Shanghai East Hospital, School of Life Science and Technology, Tongji University, 200092, Shanghai, China.
Department of Hepatology, Shanghai East Hospital, Tongji University School of Medicine, 200120, Shanghai, China.
Cell Death Dis. 2018 Feb 15;9(3):253. doi: 10.1038/s41419-018-0305-7.
Maternally expressed gene 3 (MEG3) encodes an lncRNA which is suggested to function as a tumor suppressor and has been showed to involve in a variety of cancers. Herein, our findings demonstrate that MEG3 inhibits the malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, MEG3 promotes the expression and maturition of miR122 which targets PKM2. Therefore, MEG3 decreases the expression and nuclear location of PKM2 dependent on miR122. Furthermore, MEG3 also inhibits CyclinD1 and C-Myc via PKM2 in liver cancer cells. On the other hand, MEG3 promotes β-catenin degradation through ubiquitin-proteasome system dependent on PTEN. Strikingly, MEG3 inhibits β-catenin activity through PKM2 reduction and PTEN increase. Significantly, we also found that excessive β-catenin abrogated the effect of MEG3 in liver cancer. In conclusion, our study for the first time demonstrates that MEG3 acts as a tumor suppressor by negatively regulating the activity of the PKM2 and β-catenin signaling pathway in hepatocarcinogenesis and could provide potential therapeutic targets for the treatment of liver cancer.
母系表达基因 3（MEG3）编码一种长链非编码 RNA，被认为具有肿瘤抑制作用，并已被证明参与多种癌症。在此，我们的研究结果表明，MEG3 可抑制肝癌细胞的恶性进展，无论是在体外还是体内。从机制上讲，MEG3 可促进 miR122 的表达和成熟，而 miR122 靶向 PKM2。因此，MEG3 依赖于 miR122 降低 PKM2 的表达和核定位。此外，MEG3 还可通过 PKM2 抑制肝癌细胞中的 CyclinD1 和 C-Myc。另一方面，MEG3 通过依赖于 PTEN 的泛素-蛋白酶体系统促进 β-连环蛋白的降解。值得注意的是，我们还发现过量的 β-连环蛋白可消除 MEG3 在肝癌中的作用。总之，我们的研究首次表明，MEG3 通过负调控 PKM2 和 β-连环蛋白信号通路在肝癌发生中的活性，发挥肿瘤抑制作用，并可为肝癌的治疗提供潜在的治疗靶点。
