Ming Zhang1,2, Jue Wang3, Yucui Jin1, Que Zheng1, Mengying Xing1, Yuting Tang1, Yunfei Ma1, Lingyun Li1, Bing Yao1, Hao Wu4, Changyan Ma5,6. 1. Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China. 2. Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China. 3. Division of Breast Surgery, the First Affiliated Hospital with Nanjing Medical University, Guangzhou Road 300, 210029, Nanjing, Jiangsu Province, P.R. China. 4. Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, 210029, Nanjing, Jiangsu Province, P.R. China. 5. Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China. cyma@njmu.edu.cn. 6. Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China. cyma@njmu.edu.cn.
Abstract
BACKGROUND: LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown. METHODS: TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan-Meier Plotter. RESULTS: We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS). CONCLUSIONS: FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.
BACKGROUND: LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown. METHODS: TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan-Meier Plotter. RESULTS: We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS). CONCLUSIONS: FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.