M2 Macrophage-Derived Exosomal lncRNA MIR4435-2HG Promotes Progression of Infantile Hemangiomas by Targeting HNRNPA1

Abstract

Zhiyu Li,1 Zhongying Cao,1 Nanxi Li,2 Luying Wang,2 Cong Fu,2 Ran Huo,1,2 Guangqi Xu,2 Chonglin Tian,2,* Jianhai Bi1– 3,* 1Department of Plastic and Aesthetic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Plastic and Aesthetic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 3Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhai Bi, Department of Plastic and Aesthetic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324, Jingwu Road, Huaiyin District, Jinan, Shandong Province, 250021, People’s Republic of China, Tel [phone], Email [email protected] Chonglin Tian, Department of Plastic and Aesthetic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, Shandong Province, 250021, People’s Republic of China, Tel [phone], Email [email protected]: Infantile hemangiomas (IHs) are commonly observed benign tumors that can cause serious complications. M2-polarized macrophages in IHs promote disease progression. In this study, we investigated the role of M2 macrophage-derived exosomal lncRNA MIR4435-2HG in IHs.Patients and Methods: Exosomes derived from M2 polarized macrophages were extracted. Next, using cell co-culture or transfection, we investigated whether M2 polarized macrophage-derived exosomes (M2-exos) can transport MIR4435-2HG to regulate the proliferation, migration, invasion, and angiogenesis of hemangioma-derived endothelial cells (HemECs). RNA-seq and RNA pull-down assays were performed to identify targets and regulatory pathways of MIR4435-2HG. We explored the possible mechanisms through which MIR4435-2HG regulates the biological function of HemECs.Results: M2-exos significantly enhanced the proliferation, migration, invasion, and angiogenesis of HemECs. Thus, HemECs uptake M2-exos and promote biological functions through the inclusion of MIR4435-2HG. RNA-seq and RNA pull-down experiments confirmed that MIR4435-2HG regulates of HNRNPA1 expression and directly binds to HNRNPA1, consequently affecting the NF-κB signal pathway.Conclusion: MIR4435-2HG of M2-exos promotes the progression of IHs and enhances the proliferation, migration, invasion, and angiogenesis of HemECs by directly binding to HNRNPA1. This study not only reveals the mechanism of interaction between M2 macrophages and HemECs, but also provides a promising therapeutic target for IHs.Graphical Abstract: Keywords: hemangioma-derived endothelial cell, infantile hemangioma, M2-polarized macrophage, MIR4435-2HG, HNRNPA1

Keywords

• hemangioma-derived endothelial cell
• infantile hemangioma
• m2-polarized macrophage
• mir4435-2hg
• hnrnpa1