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CircRHBDD1(4,5)/CCL2 mRNA interaction promotes breast cancer bone metastasis via bone metastatic niche formation
Xincheng Li1, Ruyuan Yu2, Man Li3
1Medical College of Jiaying University, Meizhou 514031, China; Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Editorial Department of Journals, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Background:
Bone metastasis is a prevalent and severe complication of breast cancer, with limited effective preventive or therapeutic strategies. Recently, circular RNA-targeted therapeutics have shown considerable promise in cancer treatment; yet their application for breast cancer-bone metastases remain infrequent. Comprehending the mechanisms underlying breast cancer-bone metastasis could provide possible targets in the future.
Methods:
The biological characteristics of circRHBDD1(4,5) were validated via Sanger sequencing, RNase R, and actinomycin D treatment, and its expression was further validated using in situ hybridization in breast cancer tissues. The impact of circRHBDD1(4,5) in bone-metastatic niche formation and bone metastasis was investigated utilizing osteoclastogenesis bone resorption pit assays and xenografted tumor models. Additionally, the mechanism underlying circRHBDD1(4,5)-mediated CCL2 mRNA stability was investigated using RNA pull-down, RNA immunoprecipitation, and enzyme-linked immunosorbent assays.
Results:
CircRHBDD1(4,5) was significantly elevated (P < 0.001) in bone-tropic metastatic breast cancer cells and bone-metastatic breast cancer tissues, which significantly enhanced osteoclastogenesis and induced the formation of bone metastatic niches by upregulating the chemokine CCL2. Mechanistically, circRHBDD1(4,5) directly interacted with CCL2 mRNA, whose expression was significantly positively correlated with immune cell infiltration and breast cancer-bone metastasis, and increased its stability and translation by recruiting the RNA-binding protein ELAVL1. Finally, treatment with locked nucleic acid (LNA) oligonucleotides, which targeted circRHBDD1(4,5) on CCL2 mRNA binding sites, namely LNA-based CMI-blockers, effectively inhibited circRHBDD1(4,5)-induced osteoclastogenesis and breast cancer-bone metastasis.
Conclusion:
We revealed a credible mechanism for circRHBDD1(4,5)-induced breast cancer-bone metastasis and hypothesized that disrupting circRHBDD1(4,5)-CCL2 mRNA interactions could be a promising strategy for treating breast cancer bone metastases.
Insights
Circular RNA circRHBDD1 promotes breast cancer bone metastasis by stabilizing CCL2 mRNA, leading to increased osteoclastogenesis. Targeting this interaction with LNA-based CMI-blockers offers a potential therapeutic strategy for bone metastases.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bone metastasis is a severe complication of breast cancer with limited treatment options.
- Circular RNAs (circRNAs) show therapeutic potential in cancer, but their role in breast cancer bone metastasis is understudied.
- Understanding the mechanisms of breast cancer bone metastasis is crucial for developing new therapeutic targets.
Purpose of the Study:
- To investigate the role of circRHBDD1 in breast cancer bone metastasis.
- To elucidate the mechanism by which circRHBDD1 influences bone metastasis.
- To evaluate the therapeutic potential of targeting circRHBDD1 for breast cancer bone metastasis.
Main Methods:
- Validated circRHBDD1 biological characteristics and expression in breast cancer tissues.
- Assessed circRHBDD1's impact on osteoclastogenesis and bone metastasis using in vitro and in vivo models.
- Investigated the mechanism of circRHBDD1-mediated CCL2 mRNA stability using RNA pull-down, RNA immunoprecipitation, and ELISA.
Main Results:
- CircRHBDD1 was significantly elevated in bone-metastatic breast cancer, enhancing osteoclastogenesis and bone niche formation by upregulating CCL2.
- CircRHBDD1 directly interacted with CCL2 mRNA, increasing its stability and translation via ELAVL1 recruitment.
- LNA-based CMI-blockers targeting circRHBDD1-CCL2 mRNA interaction effectively inhibited osteoclastogenesis and bone metastasis.
Conclusions:
- A mechanism for circRHBDD1-induced breast cancer bone metastasis was identified.
- Disrupting circRHBDD1-CCL2 mRNA interactions presents a promising therapeutic strategy for breast cancer bone metastases.
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