Targeting RNF219/α-Catenin/LGALS3 Axis Inhibits Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications

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.  Herein, we reported that HCC-secreted LGALS3 induced bone metastasis and skeletal-related events by promoting formation of bone pre-metastatic niche. We demonstrated that ubiquitin ligase RNF219-meidated α-catenin degradation prompted YAP1/β-catenin-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases.  Treatment with Verteporfin, a clinical drug for macular degeneration, decreased LGALS3 expression and effectively inhibited skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and could suggest a promising strategy for clinical intervention in HCC bone-metastasis.