Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated...

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Osteosarcomas exhibit immune resistance and metastasis, linked to elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT).
• The anti-cancer potential of vitamin D in osteosarcoma is not well understood, particularly its underlying mechanisms.

Purpose of the Study:

• To investigate the effects of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in osteosarcoma.
• To elucidate the molecular mechanisms by which vitamin D derivatives inhibit osteosarcoma growth and metastasis.

Main Methods:

• Utilized in vitro and in vivo osteosarcoma models.
• Assessed the impact of vitamin D (1,25(OH)2D) and VDR on NMD, ROS, and EMT pathways.
• Performed epigenome-wide motif and target gene analysis.
• Investigated SNAI2 knockdown effects and SOD2 localization.
• Evaluated calcipotriol efficacy in a mouse xenograft metastasis model.

Main Results:

• Vitamin D receptor (VDR) signaling initially enriched EMT genes, but 1,25(OH)2D subsequently inhibited the EMT pathway.
• Ligand-bound VDR directly downregulated SNAI2, distinguishing metastatic subtypes and influencing 1,25(OH)2D sensitivity.
• 1,25(OH)2D suppressed NMD machinery while upregulating NMD targets involved in anti-oncogenic activity, immunorecognition, and cell adhesion.
• SNAI2 knockdown revealed SOD2-mediated antioxidant responses and sensitization to 1,25(OH)2D via ROS suppression.
• Calcipotriol significantly inhibited osteosarcoma metastasis and tumor growth in vivo.

Conclusions:

• Vitamin D exerts novel anti-osteosarcoma effects by modulating NMD, ROS, and EMT signaling.
• The VDR-SNAI2 interaction and regulation of NMD targets are key mechanisms of vitamin D's action.
• Calcipotriol demonstrates therapeutic potential for inhibiting osteosarcoma metastasis and growth, warranting clinical translation.