A new study has identified the protein Gαi3 as a significant driver of bladder cancer progression, offering a potential target for future treatments. Researchers found that Gαi3 is overexpressed in bladder cancer tissues and cells, and its presence is associated with poorer patient survival and more aggressive tumour grades.
Using bioinformatics and single-cell sequencing, the team confirmed elevated Gαi3 levels specifically in cancerous epithelial cells. Further experiments revealed that Gαi3 expression is even higher in tissue samples from patients who received local treatment and in multiple bladder cancer cell lines.
Silencing Gαi3 using targeted shRNA or CRISPR/Cas9 gene editing inhibited cancer cell growth, migration, and invasion, while promoting apoptosis through activation of caspases. In contrast, overexpressing Gαi3 accelerated cell proliferation and mobility.
Mechanistically, Gαi3 activates the Akt-mTOR signalling pathway. Its silencing or knockout reduced phosphorylation of key proteins in the pathway, while its overexpression enhanced their activity. The anti-cancer effects of Gαi3 inhibition were partially reversed by reactivating the pathway using a constitutively active Akt1 mutant.
The study also uncovered a regulatory role for the transcription factor GATA4, which binds strongly to the Gαi3 promoter. Manipulating GATA4 levels directly influenced Gαi3 expression. In animal models, silencing Gαi3 significantly slowed tumour growth and increased apoptosis, reinforcing its potential as a therapeutic target. The findings position Gαi3 as a key player in bladder cancer development and progression.
Reference
Zhang L et al. Gαi3: a crucial biomarker and therapeutic target in bladder cancer. NPJ Precis Oncol. 2025 Jun 13;9(1):181
