Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling

• Published in: Molecular cancer Vol. 20; no. 1; pp. 98 - 18
• Main Authors: Xu, Yingru, Zhang, Shuxia, Liao, Xinyi, Li, Man, Chen, Suwen, Li, Xincheng, Wu, Xingui, Yang, Meisongzhu, Tang, Miaoling, Hu, Yameng, Li, Ziwen, Yu, Ruyuan, Huang, Mudan, Song, Libing, Li, Jun
• Format: Journal Article
• Language: English
• Published: England BioMed Central 29.07.2021; BMC
• Subjects: Animals; Bone cancer; Bone growth; Bone metastasis; Bone Neoplasms - diagnosis; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Bone remodeling; Bone Remodeling - genetics; Bone remodeling factor; Bone resorption; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Chromatin; circIKBKB; Circular RNA; DEAD-box RNA Helicases - metabolism; Disease Models, Animal; Eukaryotic Initiation Factor-4A - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Hybridization; I-kappa B Kinase - genetics; Immunofluorescence; Metastases; Metastasis; Mice; Models, Biological; mRNA; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; NF-κB; NF-κB protein; Osteoclastogenesis; Osteogenesis - genetics; Osteolysis; Patients; Phosphorylation; RNA, Circular; Signal Transduction - drug effects; Splicing factors; Statistical analysis; Variance analysis; Xenograft Model Antitumor Assays; China; circIKBKB; Bone remodeling factor; NF-κB; Bone metastasis; Breast cancer
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01394-8

Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.