Exosomal Circ_0125473 Drives Macrophages Polarization Toward M2 Through miR-5787/Wnt1/β-Catenin Signaling Pathway in Colorectal Cancer

Background: Accumulating studies have suggested exosomes participate in regulating cancer initiation and progression by delivering bioactive molecules during cell-to-cell communications. Exosomal circRNAs play critical roles in the intercellular communication between colorectal cancer (CRC) cells and macrophages, whereas the molecular mechanism remains largely unclear. Methods: We quantitatively measured the expression of circR_0125473 in serum samples from CRC patients. The effect of exosomal circR_0125473 on CRC cell proliferation and invasion and macrophages polarization was investigated. The molecular mechanisms underlying the oncogenesis and regulating M1/M2 balance in tumor immune microenvironment of exosomal circR_0125473 were explored in cell line models and subcutaneous tumors formation nude mice. Findings: In this study, exosomal circR_0125473 was upregulated in CRC and positively associated with CRC metastasis. Besides, exosomal circR_0125473 promoted CRC cells proliferation and invasion. CRC exosomes-derived circ_0125473 drived macrophages polarization towards M2 through miR-5787/Wnt1/β-catenin signaling pathway. Moreover, exosomal circR_0125473 also significantly promoted the growth of subcutaneous tumors in nude mice, although CRC cells were transplanted with exosomes-pretreated monocyte-derived macrophages (MDMs) subcutaneously. Accordingly, exosomes delivering circR_0125473 participates in regulating M1/M2 balance in tumor immune microenvironment, thereby influencing CRC tumorigenesis and progression. Funding: This study is supported by funds from the National Natural Science Foundation, China (82003042), Shandong Natural Science Foundation (ZR2020KC001 and ZR2019QH012), and Weifang Science and Technology Development Program, China (2019GX031 and 2019YX020). Declaration of Interest: All authors declare no competing interests. Ethical Approval: Animal studies were conducted under the government of the Animal Ethics Committee of Weifang Medical University.