Skip to main content

Advertisement

SpringerLink
Log in

N6-Methyladenosine (m6A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

N6-methyladenosine (m6A) functions as an important regulator in various human cancers, including gastric cancer. The immunotherapy targeting PD-1/PD-L1 has brought hope for advanced gastric cancer therapeutic. Here, present research aims to investigate the roles of m6A reader IGF2BP1 on gastric cancer tumor development and immune escape. Results indicated that IGF2BP1 up-regulated in the gastric cancer tissue and correlated with poor prognosis of gastric cancer patients. IGF2BP1 overexpression augmented the proliferation of co-cultured gastric cancer cells, and mitigated the CD8+ T cells mediated anti-tumor response, including IFN-γ secretion, surface PD-L1 level, and cytotoxicity of CD8+ T cells. Meanwhile, IGF2BP1 silencing exerted the opposite effects. In silico analysis revealed that there was a remarkable m6A modified site on PD-L1 mRNA. Moreover, the IGF2BP1 overexpression enhanced the stability of PD-L1 mRNA, thereby deteriorating the immune escape of gastric cancer cells. Collectively, these results describe a novel regulatory mechanism of IGF2BP1 by regulating PD-L1 through m6A epigenetic modification, which might provide insights for gastric cancer immunotherapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

No research data shared.

References

  1. Correa, P. (2013). Gastric cancer: Overview. Gastroenterology Clinics of North America, 42, 211–217.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Karimi, P., Islami, F., Anandasabapathy, S., Freedman, N. D., & Kamangar, F. (2014). Gastric cancer: Descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology, 23, 700–713.

    Article  Google Scholar 

  3. Petryszyn, P., Chapelle, N., & Matysiak-Budnik, T. (2020). Gastric cancer: Where are we heading? Digestive Diseases (Basel, Switzerland), 38, 280–285.

    Article  PubMed  Google Scholar 

  4. Smyth, E. C., Nilsson, M., Grabsch, H. I., van Grieken, N. C., & Lordick, F. (2020). Gastric cancer. The Lancet (London, England), 396, 635–648.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao, Q., Cao, L., Guan, L., Bie, L., Wang, S., Xie, B., Chen, X., Shen, X., & Cao, F. (2019). Immunotherapy for gastric cancer: Dilemmas and prospect. Briefings in Functional Genomics, 18, 107–112.

    Article  CAS  PubMed  Google Scholar 

  6. Chen, D. S., & Mellman, I. (2017). Elements of cancer immunity and the cancer–immune set point. Nature, 541, 321–330.

    Article  CAS  PubMed  Google Scholar 

  7. Jiang, X., Wang, J., Deng, X., Xiong, F., Ge, J., Xiang, B., Wu, X., Ma, J., Zhou, M., Li, X., Li, Y., Li, G., Xiong, W., Guo, C., & Zeng, Z. (2019). Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Molecular Cancer, 18, 10.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wu, Q., You, L., Nepovimova, E., Heger, Z., Wu, W., Kuca, K., & Adam, V. (2022). Hypoxia-inducible factors: Master regulators of hypoxic tumor immune escape. Journal of Hematology & Oncology, 15, 77.

    Article  CAS  Google Scholar 

  9. Chen, Y., Miao, L., Lin, H., Zhuo, Z., & He, J. (2022). The role of m6A modification in pediatric cancer. Biochimica et Biophysica Acta. Reviews on Cancer, 1877, 188691.

    Article  CAS  PubMed  Google Scholar 

  10. Guan, Q., Lin, H., Miao, L., Guo, H., Chen, Y., Zhuo, Z., & He, J. (2022). Functions, mechanisms, and therapeutic implications of METTL14 in human cancer. Journal of Hematology & Oncology, 15, 13.

    Article  CAS  Google Scholar 

  11. Li, Y., Su, R., Deng, X., Chen, Y., & Chen, J. (2022). FTO in cancer: Functions, molecular mechanisms, and therapeutic implications. Trends in Cancer, 8, 598–614.

    Article  PubMed  Google Scholar 

  12. Liao, J., Wei, Y., Liang, J., Wen, J., Chen, X., Zhang, B., & Chu, L. (2022). Insight into the structure, physiological function, and role in cancer of m6A readers—YTH domain-containing proteins. Cell Death Discovery, 8, 137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu, Y., Gong, C., Li, Z., Liu, J., Chen, Y., Huang, Y., Luo, Q., Wang, S., Hou, Y., Yang, S., & Xiao, Y. (2022). Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification. Molecular Cancer, 21, 34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, L., Wan, Y., Zhang, Z., Jiang, Y., Gu, Z., Ma, X., Nie, S., Yang, J., Lang, J., Cheng, W., & Zhu, L. (2021). IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A -dependent manner and promotes endometrial cancer progression. Theranostics, 11, 1100–1114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xue, T., Liu, X., Zhang, M., Qiukai, E., Liu, S., Zou, M., Li, Y., Ma, Z., Han, Y., Thompson, P., & Zhang, X. (2021). PADI2-catalyzed MEK1 citrullination activates ERK1/2 and promotes IGF2BP1-mediated SOX2 mRNA stability in endometrial cancer. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 8, 2002831.

    CAS  PubMed  Google Scholar 

  16. Zhu, P., He, F., Hou, Y., Tu, G., Li, Q., Jin, T., Zeng, H., Qin, Y., Wan, X., Qiao, Y., Qiu, Y., Teng, Y., & Liu, M. (2021). A novel hypoxic long noncoding RNA KB-1980E6. 3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability. Oncogene, 40, 1609–1627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shen, Q., Xu, Z., Sun, G., Wang, H., & Zhang, L. (2022). TFAP4 activates IGF2BP1 and promotes progression of non–small cell lung cancer by stabilizing TK1 expression through m6A modification. Molecular Cancer Research: MCR, 20, 1763–1775.

    Article  CAS  PubMed  Google Scholar 

  18. Huang, X., Zhang, H., Guo, X., Zhu, Z., Cai, H., & Kong, X. (2018). Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer. Journal of Hematology & Oncology, 11, 88.

    Article  Google Scholar 

  19. Tanprasert, P., Limpakan Yamada, S., Chattipakorn, S. C., Chattipakorn, N., & Shinlapawittayatorn, K. (2022). Targeting mitochondria as a therapeutic anti-gastric cancer approach. Apoptosis: An International Journal on Programmed Cell Death, 27, 163–183.

    Article  CAS  PubMed  Google Scholar 

  20. Dörflinger, B., Badr, M. T., Haimovici, A., Fischer, L., Vier, J., Metz, A., Eisele, B., Bronsert, P., Aumann, K., Höppner, J., Waguia Kontchou, C., Parui, I., Weber, A., Kirschnek, S., & Häcker, G. (2022). Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection. Cell Death and Differentiation, 29, 2218–2232.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu, H. T., Zou, Y. X., Zhu, W. J., Sen, L., Zhang, G. H., Ma, R. R., Guo, X. Y., & Gao, P. (2022). IncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus. Cell Death and Differentiation, 29, 627–641.

    Article  CAS  PubMed  Google Scholar 

  22. Liu, J., Li, Z., Cheang, I., Li, J., & Zhou, C. (2022). RNA-binding protein IGF2BP1 associated with prognosis and immunotherapy response in lung adenocarcinoma. Frontiers in Genetics, 13, 777399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. You, Y., Fu, Y., Huang, M., Shen, D., Zhao, B., Liu, H., Zheng, Y., & Huang, L. (2022). Recent advances of m6A demethylases inhibitors and their biological functions in human diseases. International Journal of Molecular Sciences, 23, 5815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, Y., Zheng, L., Shang, W., Yang, Z., Li, T., Liu, F., Shao, W., Lv, L., Chai, L., Qu, L., Xu, Q., Du, J., Liang, X., Zeng, J., & Jia, J. (2022). Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer. Cell Death and Differentiation, 29, 2190–2202.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li, Z. X., Zheng, Z. Q., Yang, P. Y., Lin, L., Zhou, G. Q., Lv, J. W., Zhang, L. L., Chen, F., Li, Y. Q., Wu, C. F., Li, F., Ma, J., Liu, N., & Sun, Y. (2022). WTAP-mediated m6A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis. Cell Death and Differentiation, 29, 1137–1151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, Q., Chen, C., Ding, Q., Zhao, Y., Wang, Z., Chen, J., Jiang, Z., Zhang, Y., Xu, G., Zhang, J., Zhou, J., Sun, B., Zou, X., & Wang, S. (2020). METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut, 69, 1193–1205.

    Article  CAS  PubMed  Google Scholar 

  27. Liu, X., Xiao, M., Zhang, L., Li, L., Zhu, G., Shen, E., Lv, M., Lu, X., & Sun, Z. (2021). The m6A methyltransferase METTL14 inhibits the proliferation, migration, and invasion of gastric cancer by regulating the PI3K/AKT/mTOR signaling pathway. Journal of Clinical Laboratory Analysis, 35, e23655.

    Article  CAS  PubMed  Google Scholar 

  28. Müller, S., Glaß, M., Singh, A. K., Haase, J., Bley, N., Fuchs, T., Lederer, M., Dahl, A., Huang, H., Chen, J., Posern, G., & Hüttelmaier, S. (2019). IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A-and miRNA-dependent manner. Nucleic Acids Research, 47, 375–390.

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by Natural Science Foundation of Shandong Province (No. ZR2021MH240, Lili Cao) and Natural Science Foundation of Shandong Province (No. ZR2020MH329, Yanbin Xu).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Zibo Central Hospital, Zibo, 255036, China

    Bingxi Tang

  2. Department of Clinical Laboratory, Zibo Central Hospital, Zibo, 255036, China

    Lei Bi & Xinli Li

  3. Department of General Surgery, Zibo Central Hospital, Zibo, 255036, China

    Yanbin Xu

  4. Department of Oncology, Zibo Central Hospital, Zibo, 255036, China

    Lili Cao

Authors
  1. Bingxi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanbin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lili Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xinli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lili Cao or Xinli Li.

Ethics declarations

Conflict of interest

All authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 17 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, B., Bi, L., Xu, Y. et al. N6-Methyladenosine (m6A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1. Mol Biotechnol (2023). https://doi.org/10.1007/s12033-023-00896-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12033-023-00896-8

Keywords

Search

Navigation