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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma

“…The statistical analysis of the results of qRT-PCR of clinical samples also showed a negative correlation between the expression of circ-MTHFD1L and miR-615-3p in PDAC tissues. The abnormal expression of miR-615-3p has been confirmed to be related to the occurrence and development of gastric cancer, breast cancer, and non-small cell lung cancer [ 15 – 17 ]. However, there are no reports about it and pancreatic cancer globally.…”

“…The unique circular structure of circRNAs gives them inherent resistance to exonuclease degradation and is more stable than linear RNA [ 13 ]. In recent years, extensive studies have found that circRNAs play a key role in tumorigenesis by acting as competing endogenous RNAs, such as liver cancer [ 14 ], lung cancer [ 15 ], Gastric cancer [ 16 ], breast cancer [ 17 ]. Therefore, circRNAs have great potential as a valuable tumor diagnostic biomarker or therapeutic target [ 18 ].…”

Identification of tumor antigens and immune subtypes in lower grade gliomas for mRNA vaccine development

“…Immune checkpoints (ICPs)- and immunogenic cell death modulators (ICDs)-related genes were obtained from the previous studies[ 7 , 22 ]. Then the expression level of ICPs and ICDs were compared among different immune subtypes by Pairwise t-tests[ 23 ].…”

“…Tumor antigen with or without adjuvant is the main component of a typical cancer vaccine, assisting immune cells in recognizing and eliminating cancer cells [ 7 ]. The advantages were minimal non-specific effect, non-toxic, long-term immune memory and wide treatment window for tumor vaccine treatment which could overcome the limits of drug resistance, high costs, limited therapeutic effects and other possible adverse reactions associated with traditional immunotherapy and chemotherapy [ 8 ].…”

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

“…CircRNAs can bind directly to RBPs to form RNA-protein complexes to regulate RBPs and further affect the expression and biology of downstream proteins ( Huang et al, 2020 ; Feng J. et al, 2021 ; Chen J. et al, 2021 ; Xu et al, 2021 ). Muscleblind-like (MBL) binds to exon 2 of its parental gene and induces cyclization to form circMbl, which also binds to MBL to reduce MBL abundance, thereby reducing circMbl production ( Ashwal-Fluss et al, 2014 ).…”