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Cited by 55Circular RNAs in diseasesCancer Immunotherapy and BiomarkersCancer-related molecular mechanisms research

CircRHBDD1 promotes immune escape via IGF2BP2/PD-L1 signaling and acts as a nanotherapeutic target in gastric cancer

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Li, Yanna, Wang, Zhixiong, Gao, Peng, Cao, Danping, Dong, Runyu, Zhu, Menglin, Fei, Yao, Zuo, Xueliang +1 more·2024·Journal of Translational Medicine
DOI 10.1186/s12967-024-05498-9PMC PMC11289934
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Abstract

Background: Circular RNAs (circRNAs) have been implicated in the development and progression of gastric cancer (GC). However, it remains unclear whether dysregulated circRNA affects immune escape and the efficacy of immunotherapy in GC. Our aim is to investigate the molecular mechanism of circRNA affecting GC immunotherapy and identify effective molecular therapeutic targets. Methods: The differential expression profile of circRNAs was established through circRNA sequencing, comparing three paired GC tissues with their adjacent non-cancerous gastric tissues. The expression level of circRHBDD1 in GC tissues was then assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological characteristics of circRHBDD1 were verified through a series of experiments, including agarose gel electrophoresis assays, RNase R treatment, and actinomycin D experiments. The prognostic value of circRHBDD1 in GC was evaluated by conducting both univariate and multivariate survival analyses. Furthermore, loss- and gain-of-function approaches were utilized to investigate the impact of circRHBDD1 on GC immune escape. RNA-sequencing, immunoprecipitation, flow cytometry, and methylated RNA immunoprecipitation (meRIP) analysis were performed to elucidate the underlying molecular mechanisms. Results: We discovered that circRHBDD1 exhibited remarkably high expression levels in GC tissues and cell lines. Notably, the high expression of circRHBDD1 was significantly correlated with poor overall survival and disease-free survival among GC patients. Both in vitro and in vivo experiments revealed that circRHBDD1 upregulated the expression of PD-L1 and impeded the infiltration of CD8 + T cells. Further, we found that circRHBDD1 binds to IGF2BP2, disrupting the interaction between E3 ligase TRIM25 and IGF2BP2, and ultimately inhibiting IGF2BP2 ubiquitination and degradation. Intriguingly, IGF2BP2 enhances PD-L1 mRNA stability through m 6 A modification. Additionally, we developed Poly (lactide-co-glycolic acid) (PLGA)-Polyethylene glycol (PEG)-based nanoparticles loaded with circRHBDD1 siRNA. In vivo experiments validated that the combination of PLGA-PEG(si-circRHBDD1) and anti-PD-1 offers a safe and efficacious nano-drug regimen for cancer immunotherapy. Conclusion: Our results demonstrated that circRHBDD1 promoted GC immune escape by upregulating the expression of PD-L1 and reprogramming T cell-mediated immune response. Inhibition of circRHBDD1 expression could potentially enhance the response of GC patients to immunotherapy, thus improving treatment outcomes. Additionally, the development of a nanodrug delivery system provides a feasible approach for future clinical applications.

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  • Gastric tumors exploit the ability of IMP2 to stabilize PD-L1 mRNA to facilitate immune escape, a process mediated through its interaction with the circular RNA circRHBDD1.

    “Gastric tumors exploit the ability of IMP2 to stabilize PD-L1 mRNA to facilitate immune escape, a process mediated through its interaction with the circular RNA circRHBDD1 [124].”

    From IMPlications of IMP2 in RNA Biology and Disease (2025) · cites this paper as [124]

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Cited by

Sorted by citations

  • IMPlications of IMP2 in RNA Biology and Disease

    Das, J., Busia-Bourdain, O., Khan, K. M., & Wolfe, A. L. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062415 · Cited by 3 · see citing works

    “…tumor growth and increased immune cell infiltration, highlighting the role of IMP2 in immune activation in NSCLC. Gastric tumors exploit the ability of IMP2 to stabilize PD-L1 mRNA to facilitate immune escape, a process mediated through its interaction with the circular RNA cir-cRHBDD1 [124].”

Authors
Li, Y., Wang, Z., Gao, P., Cao, D., Dong, R., Zhu, M., Fei, Y., Zuo, X., & Cai, J.
Affiliations
Wannan Medical College (CN)
Corresponding author
  • Zuo, Xueliang
  • Cai, Juan
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2024-07-30
Volume
22
Issue
1
Pages
704-704
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-024-05498-9
PMC
PMC11289934
OpenAlex
W4401120982
Cited by
55
References
3
Citations by year
2026: 26 · 2025: 26 · 2024: 3
FWCI
7.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82103293)
  • Science and Technology Project of Wuhu City (2022jc52)
  • Natural Science Foundation of Anhui Education Department for Excellent Young Scholars (2022AH030123)
  • Funding of “Peak” Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (GF2019G17, GF2019J08)
  • Support Plan for Outstanding Young Talents of Anhui Education Department (gxyq2021257)
  • Natural Science Foundation of Anhui Education Department for Distinguished Young Scholars (2022AH020074)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
circular RNA, gastric cancer, tumor immune evasion, PD-L1, IGF2BP2, TRIM25, m6A RNA methylation, PLGA-PEG nanoparticles, anti-PD-1 therapy, CD8+ T cell infiltration, prognostic factors
MeSH terms
RNA, Circular, Animals, Female, Humans, Male, Mice, Nude, Middle Aged, Prognosis, Serine Endopeptidases, Stomach Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Tumor Escape, Cell Line, Tumor, Mice, B7-H1 Antigen

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