State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, P.R. China.
School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China.
Mol Ther Nucleic Acids. 2023 Jun 19;33:164-179. doi: 10.1016/j.omtn.2023.06.013. eCollection 2023 Sep 12.
We have shown previously that polymorphism of activating transcription factor 6 (ATF6) is associated with susceptibility to hepatocellular carcinoma (HCC). Therefore, genes down-regulated by ATF6 might play a tumor-suppressing role. In the present study, we identified that expression of protein phosphatase magnesium- or manganous-dependent 1H (PPM1H) mRNA and protein can be inhibited by ATF6 in hepatoma cells and mice with liver knockdown. Tumor tissues from 134 HCC patients were analyzed by immunohistochemistry, and PPM1H exhibited higher expression levels in adjacent para-cancer tissues than in HCC tissues. Therefore, patients with higher expression of PPM1H had a better prognosis. PPM1H inhibited proliferation, migration, and invasion of hepatoma cells. In addition, PPM1H inhibited induced HCC nodule formation as well as tumor xenograft growth in diethylnitrosamine/CCl-induced HCC mouse model and nude mouse tumorigenicity assay, respectively. A 3D model of PPM1H was obtained by homology multi-template modeling, and ribosomal protein S6 kinase B1 (RPS6KB1) in the bone morphogenetic protein (BMP)/transforming growth factor β (TGF-β) pathway was screened out as the potential substrate of PPM1H by Rosetta. PPM1H could directly dephosphorylate p-RPS6KB1. To conclude, we discovered RPS6KB1 as a new PPM1H dephosphorylation substrate. PPM1H exhibited a suppressive effect on HCC progression by dephosphorylating p-RPS6KB1.
我们之前已经证明，激活转录因子 6（ATF6）的多态性与肝细胞癌（HCC）的易感性有关。因此，ATF6 下调的基因可能发挥肿瘤抑制作用。在本研究中，我们发现蛋白磷酸酶镁或锰依赖性 1H（PPM1H）mRNA 和蛋白的表达可被肝癌细胞和肝敲低小鼠中的 ATF6 抑制。通过免疫组织化学分析了 134 例 HCC 患者的肿瘤组织，发现 PPM1H 在癌旁组织中的表达水平高于 HCC 组织。因此，PPM1H 表达较高的患者预后较好。PPM1H 抑制肝癌细胞的增殖、迁移和侵袭。此外，PPM1H 分别抑制二乙基亚硝胺/CCl4 诱导的 HCC 小鼠模型中的 HCC 结节形成和裸鼠肿瘤发生试验中的肿瘤异种移植物生长。通过同源多模板建模获得了 PPM1H 的 3D 模型，并通过 Rosetta 筛选出骨形态发生蛋白（BMP）/转化生长因子 β（TGF-β）通路中的核糖体蛋白 S6 激酶 B1（RPS6KB1）作为 PPM1H 的潜在底物。PPM1H 可以直接去磷酸化 p-RPS6KB1。总之，我们发现 RPS6KB1 是 PPM1H 的一个新的去磷酸化底物。PPM1H 通过去磷酸化 p-RPS6KB1 对 HCC 进展起到抑制作用。
