WYC-209 inhibited GC malignant progression by down-regulating WNT4 through RARα

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gastric cancer (GC) presents a significant global health challenge, exacerbated by multidrug resistance.
• Existing chemotherapeutic options for GC are limited, necessitating novel treatment strategies.
• WYC-209 has shown potential in suppressing tumor growth and metastasis, but its efficacy in GC was unexplored.

Purpose of the Study:

• To investigate the anti-cancer effects of WYC-209 on gastric cancer cells in vitro and in vivo.
• To elucidate the molecular mechanisms underlying WYC-209's action in GC.
• To identify potential therapeutic targets for GC treatment.

Main Methods:

• In vitro assays: MTT, colony formation, and transwell assays to assess proliferation, colony growth, and cell mobility.
• Molecular analyses: Western blotting, qRT-PCR, RNA-seq, and enrichment analyses to detect gene and protein expression and pathways.
• In vivo studies: Xenograft models in mice.
• Mechanism validation: Dual-luciferase reporter assays and Chromatin immunoprecipitation.

Main Results:

• WYC-209 exhibited significant anti-cancer activity against GC cells both in vitro and in vivo.
• RNA-seq analysis revealed significant downregulation of Wnt family member 4 (WNT4) by WYC-209.
• Overexpression of WNT4 counteracted the inhibitory effects of WYC-209, indicating WNT4's critical role.
• WYC-209 was found to enhance the binding of retinoic acid receptor alpha (RARα) to the WNT4 promoter.

Conclusions:

• WYC-209 demonstrates potent anti-tumor efficacy in gastric cancer through the downregulation of WNT4.
• The mechanism involves RARα-mediated transcriptional repression of WNT4.
• WYC-209 represents a promising therapeutic agent for gastric cancer, targeting the RARα/WNT4 pathway.