RARG promotes gastric cancer progression by activating PMEPA1 transcription and Wnt/β-catenin signalling.

OBJECTIVE

Gastric cancer (GC) has a complex pathogenesis driven by infection, genetic mutations, epigenetic reprogramming, and tumor microenvironment (TME) remodelling, all of which contribute to tumorigenesis, metastasis, and immune evasion. Retinoic acid receptor gamma (RARG) is implicated in many cancers, but its role in GC remains unclear. This study investigates the function of RARG in GC and explores its underlying regulatory mechanisms.

METHODS

Transcription factor prediction and CUT&Tag sequencing were used to identify upstream regulators of PMEPA1. RARG expression in GC was assessed by western blotting and immunohistochemistry (IHC). The impact of RARG on GC via PMEPA1 was evaluated through functional assays. The mechanism of RARG in GC was further analysed using single-cell RNA sequencing (scRNA-seq) and validated in vitro and in vivo.

RESULTS

We identify RARG as a transcriptional regulator of PMEPA1 and show that RARG abundance is elevated in GC epithelial cells and associated with poorer overall survival. RARG depletion suppressed GC cell proliferation, invasion, and migration, whereas PMEPA1 re-expression partially rescued these phenotypes. Additionally, RARG directly binds β-catenin to promote its nuclear accumulation, consistent with enhanced Wnt/β-catenin signalling.

CONCLUSION

RARG overexpression promotes GC progression by transcriptionally activating PMEPA1 via a genomic mechanism and, in parallel, directly binding β-catenin to enhance Wnt/β-catenin signalling.