Epithelial-mesenchymal transition induced by GRO-α-CXCR2 promotes bladder cancer recurrence after intravesical chemotherapy

Non-muscle invasive bladder cancers (NMIBC) are typically treated by transurethral resection with intravesical chemotherapy. However, the post-therapeutic incidence of tumor recurrence and progression to muscle invasive disease is high, and the underlying mechanism(s) remains unknown. In this study, we observed that recurrent bladder cancer cells exhibit a mesenchymal phenotype, which is initiated by the autocrine GRO-alpha signaling. Mechanically, the chemotherapeutic drug epidoxorubicin induces GRO-alpha expression in primary bladder cancer cells at G1/S phase via p38-dependent activation of NF-kappa B. GRO-alpha phosphorylation of Snail on Ser246 supports Snail's accumulation in the nucleus, and thereby promotes transcription repression activity of Snail from E-cadherin promoters. In accordance, disrupting the GRO-alpha-Snail axis in NMIBC represents a promising alternative to prevent post-therapeutic tumor progression and recurrence.