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CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies

Oncogene volume 41, pages 4591–4605 (2022)Cite this article

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Abstract

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.

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Fig. 1: CPEB3 is downregulated in human GC cell lines and tissues, and its low-expression is correlated with poor prognosis.
Fig. 2: CPEB3 suppresses GC proliferation and metastasis both in vitro and in vivo.
Fig. 3: ADAR1 is a novel target of CPEB3.
Fig. 4: CPEB3 inhibits the translation of ADAR1 mRNA by localizing them to P bodies.
Fig. 5: CPEB3 exerts its function by suppressing ADAR1-mediated RNA editing.
Fig. 6: The AAV9-CPEB3 inhibits GC growth and metastasis in vivo (Part I).
Fig. 7: The AAV9-CPEB3 inhibits GC growth and metastasis in vivo (Part II).
Fig. 8: ADAR1-mediated RNA editing is restrained by CPEB3 in PDX tumors and human GC tissues.

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Data availability

The RNA-seq data of HGC-27-Vec and HGC-27-CPEB3 cells generated in this study have been deposited in the NCBI Sequence Read Archive (accession: PRJNA816995). The RIP-seq data generated in this study have been deposited in the NCBI Sequence Read Archive (accession: PRJNA817180). The RNA-seq data used in this study downloaded from the TCGA database and GEO database (GEO accession code: GSE84437) are publicly available. Other source data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71:264–79.

    Article  PubMed  Google Scholar 

  3. Hentze MW, Castello A, Schwarzl T, Preiss T. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Bio. 2018;19:327–41.

    Article  CAS  Google Scholar 

  4. Gebauer F, Schwarzl T, Valcarcel J, Hentze MW. RNA-binding proteins in human genetic disease. Nat Rev Genet. 2021;22:185–98.

    Article  CAS  PubMed  Google Scholar 

  5. Gerstberger S, Hafner M, Tuschl T. A census of human RNA-binding proteins. Nat Rev Genet. 2014;15:829–45.

    Article  CAS  PubMed  Google Scholar 

  6. Brannan KW, Chaim IA, Marina RJ, Yee BA, Kofman ER, Lorenz DA, et al. Robust single-cell discovery of RNA targets of RNA-binding proteins and ribosomes. Nat Methods. 2021;18:507–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pereira B, Billaud M, Almeida R. RNA-binding proteins in cancer: old players and new actors. Trends Cancer. 2017;3:506–28.

    Article  CAS  PubMed  Google Scholar 

  8. Wang E, Lu SX, Pastore A, Chen X, Imig J, Chun-Wei Lee S, et al. Targeting an RNA-binding protein network in acute myeloid leukemia. Cancer Cell. 2019;35:369–84.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chan THM, Qamra A, Tan KT, Guo J, Yang H, Qi L, et al. ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer. Gastroenterology. 2016;151:637–50.

    Article  CAS  PubMed  Google Scholar 

  10. Richter JD. CPEB: a life in translation. Trends Biochem Sci. 2007;32:279–85.

    Article  CAS  PubMed  Google Scholar 

  11. D’Ambrogio A, Nagaoka K, Richter JD. Translational control of cell growth and malignancy by the CPEBs. Nat Rev Cancer. 2013;13:283–90.

    Article  PubMed  Google Scholar 

  12. Zhong Q, Fang Y, Lai Q, Wang S, He C, Li A, et al. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling. J Exp Clin Cancer Res. 2020;39:132.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang H, Zou C, Qiu Z, Fang E, Li Q, Chen M, et al. CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression. Cell Death Dis. 2020;11:792.

  14. Luo N, Wang Z. TRIM11 stimulates the proliferation of gastric cancer through targeting CPEB3/EGFR axis. J Buon. 2020;25:2097–104.

    PubMed  Google Scholar 

  15. Mori T, Fujiwara Y, Yano M, Tamura S, Yasuda T, Takiguchi S, et al. Experimental study to evaluate the usefulness of S-1 in a model of peritoneal dissemination of gastric cancer. Gastric Cancer. 2003;6(Suppl 1):13–8.

    Article  PubMed  Google Scholar 

  16. Ford L, Ling E, Kandel ER, Fioriti L. CPEB3 inhibits translation of mRNA targets by localizing them to P bodies. Proc Natl Acad Sci USA. 2019;116:18078–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qin Y, Qiao J, Chan THM, Zhu Y, Li F, Liu H, et al. Adenosine-to-Inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Res. 2014;74:840–51.

    Article  CAS  PubMed  Google Scholar 

  18. Chan THM, Lin CH, Qi L, Fei J, Li Y, Yong KJ, et al. A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut. 2014;63:832–43.

    Article  CAS  PubMed  Google Scholar 

  19. Crews LA, Jiang Q, Zipeto MA, Lazzari E, Court AC, Ali S, et al. An RNA editing fingerprint of cancer stem cell reprogramming. J Transl Med. 2015;13:52.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Okugawa Y, Toiyama Y, Shigeyasu K, Yamamoto A, Shigemori T, Yin C, et al. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. J Transl Med. 2018;16:366.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Youn JY, Dyakov B, Zhang J, Knight J, Vernon RM, Forman-Kay JD, et al. Properties of stress granule and P-body proteomes. Mol Cell. 2019;76:286–94.

    Article  CAS  PubMed  Google Scholar 

  22. Eulalio A, Behm-Ansmant I, Izaurralde E. P bodies: at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Bio. 2007;8:9–22.

    Article  CAS  Google Scholar 

  23. Yang Z, Jakymiw A, Wood MR, Eystathioy T, Rubin RL, Fritzler MJ, et al. GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation. J Cell Sci. 2004;117:5567–78.

    Article  CAS  PubMed  Google Scholar 

  24. Rehwinkel J. A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA. 2005;11:1640–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wienken CJ, Baaske P, Rothbauer U, Braun D, Duhr S. Protein-binding assays in biological liquids using microscale thermophoresis. Nat Commun. 2010;1:100

    Article  PubMed  Google Scholar 

  26. Zipeto MA, Court AC, Sadarangani A, Delos Santos NP, Balaian L, Chun H, et al. ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell. 2016;19:177–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ramírez-Moya J, Baker AR, Slack FJ, Santisteban P. ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity. Oncogene. 2020;39:3738–53.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Watanabe M, Nasu Y, Kashiwakura Y, Kusumi N, Tamayose K, Nagai A, et al. Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth. Hum Gene Ther. 2005;16:699–710.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Y, Ma H, Zhang J, Liu S, Liu Y, Zheng D. AAV-mediated TRAIL gene expression driven by hTERT promoter suppressed human hepatocellular carcinoma growth in mice. Life Sci. 2008;82:1154–61.

    Article  CAS  PubMed  Google Scholar 

  30. Kamiya A, Hayama Y, Kato S, Shimomura A, Shimomura T, Irie K, et al. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat Neurosci. 2019;22:1289–305.

    Article  CAS  PubMed  Google Scholar 

  31. Lunde BM, Moore C, Varani G. RNA-binding proteins: modular design for efficient function. Nat Rev Mol Cell Bio. 2007;8:479–90.

    Article  CAS  Google Scholar 

  32. Tan P, Yeoh K. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149:1153–62.

    Article  CAS  PubMed  Google Scholar 

  33. Yao F, Kausalya JP, Sia YY, Teo ASM, Lee WH, Ong AGM, et al. Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep. 2015;12:272–85.

    Article  CAS  PubMed  Google Scholar 

  34. Wang K, Yuen ST, Xu J, Lee SP, Yan HHN, Shi ST, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46:573–82.

    Article  CAS  PubMed  Google Scholar 

  35. Han S, Kim H, Shin J, Jeong E, Lee W, Kim KY, et al. RNA editing in RHOQ promotes invasion potential in colorectal cancer. J Exp Med. 2014;211:613–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han L, Diao L, Yu S, Xu X, Li J, Zhang R, et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell. 2015;28:515–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep. 2015;13:267–76.

    Article  CAS  PubMed  Google Scholar 

  38. Fritzell K, Xu L, Lagergren J, Öhman M. ADARs and editing: the role of A-to-I RNA modification in cancer progression. Semin Cell Dev Biol. 2018;79:123–30.

    Article  CAS  PubMed  Google Scholar 

  39. Shiromoto Y, Sakurai M, Minakuchi M, Ariyoshi K, Nishikura K. ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells. Nat Commun. 2021;12:1654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen L, Li Y, Lin CH, Chan THM, Chow RKK, Song Y, et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med. 2013;19:209–16.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhao W, Cao L, Ying H, Zhang W, Li D, Zhu X, et al. Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition. Cell Res. 2019;29:895–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee JE, Cathey PI, Wu H, Parker R, Voeltz GK. Endoplasmic reticulum contact sites regulate the dynamics of membraneless organelles. Science. 2020;367:eaay7108.

    Article  PubMed  Google Scholar 

  43. Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020;21:255–72.

    Article  CAS  PubMed  Google Scholar 

  44. Wang D, Tai P, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18:358–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, et al. JOSD1 inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing MCL1. Cell Death Differ. 2020;27:55–70.

    Article  CAS  PubMed  Google Scholar 

  46. Ballesteros-Briones MC, Martisova E, Casales E, Silva-Pilipich N, Buñuales M, Galindo J, et al. Short-term local expression of a PD-L1 blocking antibody from a self-replicating RNA vector induces potent antitumor responses. Mol Ther. 2019;27:1892–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chowdhury EA, Meno-Tetang G, Chang HY, Wu S, Huang HW, Jamier T, et al. Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models. Adv Drug Deliver Rev. 2021;170:214–37.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81802599, 81772579). We thank Prof. Zun-Fu Ke (Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University) and his colleagues for the help of pathological diagnoses and guidance. We appreciate Department of Laboratory Medicine, the First Affiliated Hospital of Sun Yat-sen University for the help of urine and serum detection. We appreciate all supports from Center for Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University.

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  1. These authors contributed equally: Jian Chen, Lu Li, Tian-Yu Liu, Hua-Feng Fu.

Authors and Affiliations

  1. Center for Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Jian Chen, Hua-Feng Fu, Ji-Shang Yu, Yu-Jian Xia, Tian-Hao Zhang, Dong-Jie Yang & Yu-Long He

  2. 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

    Lu Li

  3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Tian-Yu Liu

  4. Department of Thyroid and Breast Surgery, The Eastern Division of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Yuan-Hui Lai

  5. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Xiong Lei

  6. Department of Clinical Immunology, Institute of Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China

    Jun-Fa Xu

  7. Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China

    Yu-Long He

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Contributions

YLH, DJY and JC conceived and designed the study. JC, LL, TYL and HFF contributed to carry out the experiments. JSY, YJX and THZ provided clinical samples and clinical information. JC, LL, YHL, XL and JFX wrote the manuscript. YLH supervised the research. All authors read and approved the final manuscript.

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Correspondence to Dong-Jie Yang or Yu-Long He.

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Chen, J., Li, L., Liu, TY. et al. CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies. Oncogene 41, 4591–4605 (2022). https://doi.org/10.1038/s41388-022-02454-z

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