Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, 150081, China.
Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, China.
Cell Death Dis. 2020 Sep 23;11(9):792. doi: 10.1038/s41419-020-02984-y.
Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein. We had reported that CPEB3 is involved in hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of CPEB3 in HCC remain unclear. In this study, we firstly performed RNA immunoprecipitation to uncover the transcriptome-wide CPEB3-bound mRNAs (CPEB3 binder) in HCC. Bioinformatic analysis indicates that CPEB3 binders are closely related to cancer progression, especially HCC metastasis. Further studies confirmed that metadherin (MTDH) is a direct target of CPEB3. CPEB3 can suppress the translation of MTDH mRNA in vivo and in vitro. Besides, luciferase assay demonstrated that CPEB3 interacted with 3'-untranslated region of MTDH mRNA and inhibited its translation. Subsequently, CPEB3 inhibited the epithelial-mesenchymal transition and metastasis of HCC cells through post-transcriptional regulation of MTDH. In addition, cpeb3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis and subsequent lung metastasis. Our results also indicated that CPEB3 was a good prognosis marker, which is downregulated in HCC tissue. In conclusion, our results demonstrated that CPEB3 played an important role in HCC progression and targeting CPEB3-mediated mRNA translation might be a favorable therapeutic approach.
细胞质多聚腺苷酸化元件结合蛋白 3（CPEB3）是一种序列特异性 RNA 结合蛋白。我们曾报道 CPEB3 参与肝细胞癌（HCC）的进展。然而，CPEB3 在 HCC 中的潜在机制仍不清楚。在这项研究中，我们首先进行 RNA 免疫沉淀，以揭示 HCC 中 CPEB3 结合的转录组范围的 mRNAs（CPEB3 结合物）。生物信息学分析表明，CPEB3 结合物与癌症进展密切相关，特别是 HCC 转移。进一步的研究证实，metadherin（MTDH）是 CPEB3 的直接靶标。CPEB3 可以在体内和体外抑制 MTDH mRNA 的翻译。此外，荧光素酶测定表明 CPEB3 与 MTDH mRNA 的 3'-非翻译区相互作用并抑制其翻译。随后，CPEB3 通过对 MTDH 的转录后调节抑制 HCC 细胞的上皮-间充质转化和转移。此外，cpeb3 敲除小鼠对致癌物诱导的肝癌发生和随后的肺转移更敏感。我们的结果还表明 CPEB3 是一种预后良好的标志物，在 HCC 组织中下调。总之，我们的结果表明 CPEB3 在 HCC 进展中发挥重要作用，靶向 CPEB3 介导的 mRNA 翻译可能是一种有利的治疗方法。
