Cancer-Derived Exosomal LINC01615 Induces M2 Polarization of Tumor-Associated Macrophages via RBMX-EZH2 Axis to Promote Colorectal Cancer Progression

Anshu Li,1,* Jiaxin Hong,2,* Xianxiong Ma,1,* Yongzhou Huang,1 Qi Jiang,1 Chenggang Zhang,3 Yu Wang,4 Yongming Huang1 1Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 4Department of Gastrointestinal Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongming Huang, Email [email protected]: LncRNAs have been proved to play an important role in human cancers. The M2 polarization of tumor associated macrophages (TAMs) is also reported to promote cancer progression. However, the specific role of cancer derived exosomal lncRNA in the M2 polarization of macrophages remains largely unknown.Methods: Bioinformatic analysis was used to screen out the differentially expressed lncRNAs in colorectal cancer (CRC). Single-cell RNA sequencing was conducted to investigate the different distribution of cell type in tumor and para-tumor tissues. Function gain and loss assays were performed both in vitro and in vivo to verify the specific role of target genes. The involvement of exosomes was verified by transmission electron microscopy, nano-sight particle tracking analysis and Cre-LoxP system. RNA immunoprecipitation, RNA pull-down, truncation experiment, dual-luciferase reporter assay, chromatin immunoprecipitation, qRT-PCR and Western blot were used to explore the interactions between LINC01615, RBMX and EZH2.Results: LINC01615 was highly expressed in CRC and contributed to the M2 polarization of TAMs and progression of CRC. Mechanistically, LINC01615 could be transported from CRC cells to TAMs via exosomes. The exosomal LINC01615 acted as a scaffold to mediate the combination between RBMX and EZH2 mRNA and EZH2 promoter, which promoted EZH2 expression and M2 polarization of TAMs, thus promoting CRC progression.Conclusion: Cancer-derived exosomal LINC01615 induces M2 polarization of TAMs via RBMX-EZH2 axis to promote CRC progression, which may be a reliable diagnostic marker and potential therapeutic target for CRC.Keywords: colorectal cancer, LINC01615, EZH2, RBMX, exosome, macrophage