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Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage
Xin Huang1, Jingyu Wang1, Jibin Guan2
1Department of Nephrology, The First Hospital of China Medical University, Shenyang, China.
Background:
Macrophages are the most abundant infiltrating immune-related stromal cells present in and around tumors, showing different phenotypes and functions. M2 macrophages mainly exert immunosuppressive functions and promote tumor growth. Exosomes are emerging as important mediators of cross-talk between tumor cells and the microenvironment. CircRNAs are novel members of non-coding RNAs that regulate cancer proliferation and progression. However, the mechanism by which exosomal circRNA regulates macrophage polarization in renal cell carcinoma (RCC) is still largely unknown.
Methods:
RCC-derived exosomes were characterized using transmission electron microscopy and nanoparticle tracking analysis (NTA). CCK-8, wound healing, and Transwell assays were performed to assess whether exosomes would affect the proliferation, migration, and invasion of RCC. Furthermore, we performed a bioinformatics analysis to identify circRNAs in RCC serum-derived exosomes from the GEO database. The fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circSAFB2. Bioinformatics analyses (StarBase 2.0) were used to pool the miRNA targets of circSAFB2. Luciferase assays were performed to verify the direct interactions. Western blotting was used to detect markers of macrophage M2 polarization. Lastly, mouse xenograft and bioluminescence imaging were used to examine the clinical relevance of exosomal circSAFB2 in vivo.
Results:
We report the circRNA derived from SAFB2 and evaluate its biological function in promoting the immune escape of RCC. We found that circSAFB2 was highly expressed in RCC tissues and RCC-derived exosomes. Furthermore, we demonstrated that exosomal circSAFB2 mediates the polarization of M2 macrophages through the miR-620/JAK1/STAT3 axis to promote RCC metastasis.
Conclusions:
Our data first demonstrated that circSAFB2 leads to immune escape from RCC by mediating M2 macrophage polarization via the miR-620/JAK1/STAT3 axis. These findings indicate a novel molecular mechanism of exosomal circSAFB2 in the progression of RCC and implicate circSAFB2 as a target for exosome-mediated tumor immune evasion.
Insights
Circular RNA SAFB2 (circSAFB2) in exosomes promotes renal cell carcinoma (RCC) immune escape by polarizing M2 macrophages. This finding reveals a new mechanism for exosomal circRNA in RCC progression and offers a potential target for therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Macrophages are key stromal cells in tumors, with M2 subtypes promoting immunosuppression and tumor growth.
- Exosomes mediate intercellular communication, and circular RNAs (circRNAs) regulate cancer progression.
- The role of exosomal circRNAs in macrophage polarization in renal cell carcinoma (RCC) remains unclear.
Purpose of the Study:
- To investigate the function of exosomal circRNAs in regulating macrophage polarization in RCC.
- To identify specific circRNAs involved in RCC-derived exosome-mediated immune responses.
- To elucidate the molecular mechanisms underlying exosomal circRNA's role in RCC progression and immune evasion.
Main Methods:
- Characterization of RCC-derived exosomes and assessment of their effects on RCC cells.
- Bioinformatic analysis of serum-derived exosomal circRNAs from RCC patients.
- Validation of circSAFB2 expression, localization, and its role in M2 macrophage polarization via molecular assays and in vivo mouse models.
Main Results:
- circSAFB2 was found to be highly expressed in RCC tissues and RCC-derived exosomes.
- Exosomal circSAFB2 was shown to mediate M2 macrophage polarization.
- This polarization was linked to the miR-620/JAK1/STAT3 signaling axis, promoting RCC metastasis.
Conclusions:
- circSAFB2 facilitates immune escape in RCC by orchestrating M2 macrophage polarization through the miR-620/JAK1/STAT3 pathway.
- This study identifies a novel mechanism of exosomal circSAFB2 in driving RCC progression.
- circSAFB2 presents a potential therapeutic target for overcoming exosome-mediated tumor immune evasion in RCC.
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