Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides

Huang, Di; Zhu, Xiaofeng; Ye, Shuying; Zhang, Jiahui; Liao, Jianyou; Zhang, Ning; Zeng, Xin; Wang, Jiawen; Yang, Bing; Zhang, Yin; Lao, Liyan; Chen, Jianing; Xin, Min; Nie, Yan; Saw, Phei Er; Su, Shicheng; Song, Erwei

doi:10.1038/s41586-023-06834-7

Cited by 49 publications

(7 citation statements)

References 90 publications

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“…In recent years, circRNAs have been used for the development of vaccines against SARS-CoV-2 [ 47 ] and hard-to-treat malignancies [ 48 ], owing to their highly stable and continuously translatable properties. A recent study showed that administration of vaccines consisting of tumor-specific circRNA or its encoded peptides in mice bearing breast cancer tumors or melanoma induced enhanced infiltration of tumor-antigen-specific cytotoxic T cells, which led to effective tumor control [ 10 ]. In addition, functional circRNAs are widely used in preclinical studies to develop new therapeutic targets for tumors [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, increasing attention has been drawn towards a previously unknown protein-coding ability of specific circRNAs with N6-methyladenosine (m6A), internal ribosomal entry sites (IRES), and open reading frames (ORFs) [ 9 ]. Huang et al [ 10 ] showed that the cryptic peptides translated by circFAM53B efficiently primed naive CD4 + and CD8 + T cells in an antigen-specific manner and induced anti-tumor immunity. In a previous study, we reported that the circUBE4E-173aa novel protein encoded by circUBE4B interacts with MAPK1 to activate the MAPK/ERK signaling pathway to promote ESCC progression [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1

Lei,

Liang,

Liang

et al. 2024

J Exp Clin Cancer Res

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Background Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be involved in the regulation of the PI3K/AKT pathway, but the underlying mechanisms are unclear. Therefore, this study aimed to identify protein-coding circRNAs and investigate their functions in ESCC. Methods Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. Thereafter, LC–MS/MS was used to identify circPDE5A-encoded novel protein PDE5A-500aa. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circPDE5A and PDE5A-500aa in ESCC. Lastly, circRNA-loaded nanoplatforms were constructed to investigate the therapeutic translation value of circPDE5A. Results We found that circPDE5A expression was down-regulated in ESCC cells and tissues and that it was negatively associated with advanced clinicopathological stages and poorer prognosis in ESCC. Functionally, circPDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding PDE5A-500aa, a key regulator of the PI3K/AKT signaling pathway in ESCC. Mechanistically, PDE5A-500aa interacted with PIK3IP1 and promoted USP14-mediated de-ubiquitination of the k48-linked polyubiquitin chain at its K198 residue, thereby attenuating the PI3K/AKT pathway in ESCC. In addition, Meo-PEG-S–S-PLGA-based reduction-responsive nanoplatforms loaded with circPDE5A and PDE5A-500aa plasmids were found to successfully inhibit the growth and metastasis of ESCC in vitro and in vivo. Conclusion The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of ESCC by promoting USP14-mediated de-ubiquitination of PIK3IP1 and may serve as a potential target for the development of therapeutic agents. Graphical Abstract The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of esophageal squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1

Lei,

Liang,

Liang

et al. 2024

J Exp Clin Cancer Res

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“…In a recent study, Huang et al showed that circFAM53B, a tumor-specific circRNA, initiates anti-tumor immunity by expressing a specific peptide, underlining circRNA’s potential in immunotherapy. 62 …”

Section: Rna-based Vectors For Antigen Expressionmentioning

confidence: 99%

Recent progress in mRNA cancer vaccines

Yao,

Xie,

Xia

2024

Human Vaccines & Immunotherapeutics

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The research and development of messenger RNA (mRNA) cancer vaccines have gradually overcome numerous challenges through the application of personalized cancer antigens, structural optimization of mRNA, and the development of alternative RNA-based vectors and efficient targeted delivery vectors. Clinical trials are currently underway for various cancer vaccines that encode tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), or immunomodulators. In this paper, we summarize the optimization of mRNA and the emergence of RNA-based expression vectors in cancer vaccines. We begin by reviewing the advancement and utilization of state-of-the-art targeted lipid nanoparticles (LNPs), followed by presenting the primary classifications and clinical applications of mRNA cancer vaccines. Collectively, mRNA vaccines are emerging as a central focus in cancer immunotherapy, offering the potential to address multiple challenges in cancer treatment, either as standalone therapies or in combination with current cancer treatments.

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“…Another interesting fact about circRNA is that they are capable of encoding cryptic peptide that could serve as TSAs. 131 However, it is important to note that while these circRNA-based therapeutic platforms show promise, they do not confer a sustained therapeutic effect and lack the prophylactic efficacy characteristic of vaccines. Consequently, the development and advancement of circRNA vaccines remain in the early stages of development.…”

Section: Part 4: Rna-based Vaccinementioning

confidence: 99%

Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides

Cited by 49 publications

References 90 publications

CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1

CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1

Recent progress in mRNA cancer vaccines

Advancements in clinical RNA therapeutics: Present developments and prospective outlooks

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