N6-methyladenosine-modified circDCP2 promotes carbon black nanoparticle-induced malignancy in human bronchial epithelial cells via PI3K-AKT pathway and macrophage homeostasis

Abstract Long-term exposure to environmental carbon black nanoparticles (CBNP) has been shown to increase the risk of pulmonary malignancies. However, the role of epigenetic regulation, particularly circular RNAs (circRNAs), in this process remains poorly understood. Using whole transcriptome and RNA sequencing, we identified that circDCP2 was upregulated in CBNP-transformed cells and clinically lung cancer tissues. Moreover, circDCP2 was found to promote tumor progression both in vitro and in vivo. Mechanistically, N6-methyladenosine (m 6 A) modification of circDCP2 promotes the transcriptional upregulation of cyclin D1 (CCND1) by interacting with heterogeneous nuclear ribonucleoprotein A2/B1 (HnRNPA2B1), thereby activating the PI3K-AKT signaling pathway and promoting malignant transformation. Additionally, circDCP2 facilitates the IGF2BP3-JAK-STAT signaling pathway, which promotes the reprogramming of tumor-associated macrophages (TAMs) into the M2-type TAMs via cytokines secretion, contributing to the formation of an immunosuppressive microenvironment that further accelerates tumorigenesis and progression. Our research demonstrates that circDCP2 functions as an important regulator in promoting CBNP-induced lung carcinogenesis and may serve as a potential diagnostic biomarker and a promising therapeutic target for lung cancer patients.