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Silencing of circCRIM1 Drives IGF2BP1-Mediated NSCLC Immune Evasion
Wenbei Peng1, Linlin Ye1, Qianqian Xue1
1Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Objectives:
Circular RNAs (circRNAs) have been found to have significant impacts on non-small cell lung cancer (NSCLC) progression through various mechanisms. However, the mechanism of circRNAs modulating tumor immune evasion in NSCLC has yet to be well-revealed.
Materials And Methods:
Through analyzing the expression profiles of circRNAs in NSCLC tissues, RNA FISH, pull-down assay, mass spectrometry analysis, and RIP, circCRIM1 was identified, and its interaction with IGF2BP1 was confirmed. The effects of circCRIM1 on modulating tumor immune evasion were explored via co-culture in vitro and in tumor xenograft models. Subsequently, we evaluated the regulatory effects of circCRIM1 on IGF2BP1 and screened its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circCRIM1 could regulate the stability of target mRNA.
Results:
circCRIM1 was downregulated in NSCLC, and its expression was positively correlated with favorable prognoses. Furthermore, circCRIM1 was more stable than its linear transcript and was mainly localized in the cytoplasm. Mechanistically, circCRIM1 destabilized HLA-F mRNA via competitive binding to IGF2BP1. Importantly, the overexpression of circCRIM1 suppressed the immune evasion of NSCLC and promoted the expressions of Granzyme B, IFN-γ, and TNF-α of CD8+ T and NK cell in vitro co-culture assays and tumor xenograft models.
Conclusions:
This study identifies circCRIM1 as a new tumor suppressor that inhibits tumor immune evasion through a competitive combination with IGF2BP1 to destabilize HLA-F mRNA.
Insights
Circular CRIM1 (circCRIM1) acts as a tumor suppressor in non-small cell lung cancer (NSCLC). It inhibits immune evasion by destabilizing HLA-F mRNA, improving patient prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Circular RNAs (circRNAs) play roles in non-small cell lung cancer (NSCLC) progression.
- The precise mechanisms by which circRNAs influence tumor immune evasion in NSCLC remain unclear.
Purpose of the Study:
- To identify and characterize circRNAs involved in modulating tumor immune evasion in NSCLC.
- To elucidate the molecular mechanisms underlying circCRIM1's function in NSCLC immune evasion.
Main Methods:
- Expression profiling of circRNAs in NSCLC tissues.
- RNA FISH, pull-down assays, mass spectrometry, and RIP to identify circCRIM1 and its interacting proteins.
- In vitro co-culture and tumor xenograft models to assess circCRIM1's effects on immune evasion.
- RNA sequencing to identify circCRIM1 target genes.
Main Results:
- circCRIM1 was found to be downregulated in NSCLC and correlated with better prognoses.
- circCRIM1 acts by competitively binding to IGF2BP1, leading to the destabilization of HLA-F mRNA.
- Overexpression of circCRIM1 suppressed immune evasion and enhanced the expression of immune markers (Granzyme B, IFN-γ, TNF-α) in CD8+ T and NK cells.
Conclusions:
- circCRIM1 functions as a novel tumor suppressor in NSCLC.
- circCRIM1 inhibits tumor immune evasion by destabilizing HLA-F mRNA through interaction with IGF2BP1.
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