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Study on the Mechanism of Exosome circAP2B1 Promoting Proliferation and Metastasis of Esophageal Squamous cell carcinoma

ABSTRACT: Background: Esophageal squamous cell carcinoma (ESCC) has become an important global health issue. The M2 polarization of tumor-associated macrophages (TAMs) plays a key role in the occurrence and development of ESCC. It is reported that exosome circRNAs are involved in the regulation of the polarization state of TAMs, but the underlying mechanism remains unclear. In this study, we aim to identify novel exosome circrnas that regulate the progression of ESCC and explore their biological functions and regulatory mechanisms in ESCC. Method: The highly expressed circRNAs in ESCC tissues and plasma were identified by circRNA microarray analysis. Transmission electron microscopy, differential centrifugation and Western blotting were used for the presence of exosome circAP2B, and the uptake of circAP2B1 by macrophages was determined by exosome tracing. The effects of exosome circAP2B1 on tumor proliferation and metastasis were investigated in vitro and in vivo. The role and molecular mechanism of exosome circAP2B1 in enhancing mitochondrial homeostasis of macrophages to induce M2 polarization were investigated by means of flow cytometry analysis, IP, LC-MS/MS, RIP, Pull down, CHIP, CHRIP and dual-luciferase reporter gene. Result: We demonstrated that the upregulation of exosome circAP2B1 expression was positively correlated with lymph node metastasis and poor prognosis in patients with ESCC. Functionally, exosome circAP2B1 promotes the growth and metastasis of ESCC both in vitro and in vivo by inducing TMS-M2 polarization. Mechanism speaking, the tumor-derived exosome circAP2B1 enters macrophages to promote the nuclear translocation of the circAP2B1/ESRRA/KPNA1 ternary complex and mediate the transcriptional regulation of MFN2 to enhance the mitochondrial homeostasis of TAMs. Conclusion: The exosome circAP2B1 derived from ESCC cells induces TMS-M2 polarization and tumor progression by regulating mitochondrial metabolic reprogramming in macrophages. Therefore, circAP2B1 targeting exosome packaging may provide potential diagnostic and therapeutic strategies for ESCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296251 | GEO | 2025/05/15

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAb) and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift towards an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T-cell proliferation and IFNγ secretion. Indeed, M1-like and M2-like macrophage differentiation involves complex signaling pathways leading to specific gene expression profiles. Typically, stimuli from the TME induce pathways including JAK/STATs, MAPK, PI3K/AKT, NOTCH and NF-κB influencing TAMs polarization. We investigated the signaling pathways activated in monocytes and M-CSF-induced M2-like macrophages upon BTN2A1 engagement using anti-BTN2A mAb5. After 30 min of treatment, we observed phosphorylation of MAPKs (i.e. ERK1/2, P38 and JNK) in CD14+ monocytes and in M2-like macrophages, unlike isotype control-treated cells. In contrast, the PI3K/AKT, JAK/STAT, and NF-kB pathways were not consistently activated after 30 min of anti-BTN2A mAb5 treatment. Since BTN2A1 lacks intrinsic kinase activity, we explored whether BTN2A1 could form complexes with molecular partners in M2-like macrophages that provide kinase activity. We prepared lysates from M2-like macrophages treated with mAb5 or with its isotype control for 30 min and performed immunoprecipitation (IP) using another anti-BTN2A mAb followed by western blotting with anti-phosphoTyrosine (pTyr). A 70 kDa was co-immunoprecipitated with BTN2A1 and revealed by the anti-pTyr in lysates from anti-BTN2A mAb5-treated M2-like macrophages. To identify which Tyrosine kinase is enriched in anti-BTN2A mAb5-treated M2-like macrophages, we performed LC-MS/MS on anti-pTyr immunoprecipitates from treated cells. Several tyrosine kinases, including P38α/δ and JNK, were enriched. Notably, SYK was also identified and matched the 72kDa molecular weight of the pTyr band co-immunoprecipitated with BTN2A1.

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Study on the Mechanism of Exosome circAP2B1 Promoting Proliferation and Metastasis of Esophageal Squamous cell carcinoma

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