Exosomal Circsafb2 Reshaping Tumor Environment to Promote Renal Cell Carcinoma Progression by Mediating M2 Macrophage Polarization

Abstract

BackgroundMacrophages 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.MethodsRCC-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.ResultsWe 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.ConclusionsOur 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.

The Roles of Tumor-Associated Macrophages in Prostate Cancer

“…circCdy can also mediate M1 polarization by curbing the transportation of IRF4 into the nucleus [96]. However, circSAFB2, as a sponge for miR-620, promotes the polarization of M2 macrophages through modulating JAK1/ STAT3 axis [97]. [98].…”

Tumor-derived extracellular vesicles modulate innate immune responses to affect tumor progression

“…Lung cancer cell-derived circPVT1 increases EZH2 expression by downregulating miR-124-3p expression so that macrophages are induced to polarize towards an M2-like phenotype ( 86 ). CircSAFB2 in renal cell carcinoma cell-derived EVs functioned as a miR-620 sponge while JAK1 and STAT3 protein levels were tested markedly lower after co-culturing with miR-620 mimics ( 87 ). This correlates with the result that renal cell carcinoma cell-derived EVs induce macrophages express a higher level of JAK1 and STAT3 protein, and miR-620 can prevent the JAK1 and STAT3 expression ( 87 ).…”

“…CircSAFB2 in renal cell carcinoma cell-derived EVs functioned as a miR-620 sponge while JAK1 and STAT3 protein levels were tested markedly lower after co-culturing with miR-620 mimics ( 87 ). This correlates with the result that renal cell carcinoma cell-derived EVs induce macrophages express a higher level of JAK1 and STAT3 protein, and miR-620 can prevent the JAK1 and STAT3 expression ( 87 ). In addition, circNEIL3 has been shown to contribute to tumor progression by stabilizing the oncogenic protein IGF2BP3, which is packaged by hnRNPA2B1 in glioma cells and transported to TAMs ( 88 ).…”

Role of tumor-derived exosomes in metastasis, drug resistance and diagnosis of clear cell renal cell carcinoma

“…A new study found that CAFS-derived exosomes directly inhibit ring finger protein 43 (RNF43) expression and activate the Wnt/b-catenin signaling pathway by delivering miR-181d-5p, thereby promoting RCC stemness and progression (23). Additionally, Huang et al found that circSAFB2 delivered by ccRCC-derived exosomes mediates the polarization of M2 macrophages via the miR-620/JAK1/STAT3 axis, thereby remodeling the tumor microenvironment and ultimately promoting ccRCC metastasis (24).…”

“…Additionally, Huang et al. found that circSAFB2 delivered by ccRCC-derived exosomes mediates the polarization of M2 macrophages via the miR-620/JAK1/STAT3 axis, thereby remodeling the tumor microenvironment and ultimately promoting ccRCC metastasis ( 24 ).…”