Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Clinical Microbiology Laboratory, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China.
Oncogene. 2022 Oct;41(41):4591-4605. doi: 10.1038/s41388-022-02454-z. Epub 2022 Sep 6.
Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.
解析 RNA 结合蛋白与相应 RNA 之间的串扰将有助于更好地理解胃癌（GC）的进展。全面的生物信息学研究表明细胞质多聚腺苷酸化元件结合蛋白 3（CPEB3）可能在 GC 进展中发挥重要作用。然后我们发现 CPEB3 在 GC 中下调，并与预后相关。此外，CPEB3 在体外抑制 GC 细胞增殖、侵袭和迁移，以及体内肿瘤生长和转移。机制研究表明 CPEB3 通过结合 CPEC 核苷酸元件与 ADAR1 mRNA 的 3'-UTR 相互作用，然后通过将其定位到处理体（P 体）中来抑制其翻译，最终导致 ADAR1 介导的 RNA 编辑受到抑制。微量热泳动分析进一步表明，CPEB3 与 P 体主要成分 GW182 的直接相互作用是通过 CPEB3 的 440-698AA 区域与 GW182 的 403-860AA 区域结合实现的。最后，开发了 AAV9-CPEB3 并在小鼠模型中进行了给药，以评估其在基因治疗中的潜在价值。我们发现 AAV9-CPEB3 抑制 GC 的生长和转移。此外，AAV9-CPEB3 诱导小鼠肝脏水肿变性，但不会引起肾脏损伤。这些发现表明，CPEB3 通过将 ADAR1 mRNA 定位到 P 体来抑制 ADAR1 介导的 RNA 编辑，从而抑制 GC 的进展。
