RNF219/α-Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications.
Shuxia ZhangYingru XuChan XieLiangliang RenGeyan WuMeisongzhu YangXingui WuMiaoling TangYameng HuZiwen LiRuyuan YuXinyi LiaoShuang MoJueheng WuMengfeng LiErwei SongYanfei QiLibing SongJun LiPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2020)
The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/β-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.
Keyphrases
- bone mineral density
- bone loss
- squamous cell carcinoma
- end stage renal disease
- soft tissue
- small cell lung cancer
- bone regeneration
- free survival
- ejection fraction
- epithelial mesenchymal transition
- chronic kidney disease
- newly diagnosed
- dna methylation
- gene expression
- postmenopausal women
- body composition
- prognostic factors
- transcription factor
- induced apoptosis
- emergency department
- cell death
- long non coding rna
- optical coherence tomography
- signaling pathway
- small molecule
- smoking cessation
- patient reported
- dna repair