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-α signaling. Mechanically, the chemotherapeutic drug epidoxorubicin induces GRO-α expression in primary bladder cancer cells at G1/S phase via p38-dependent activation of NF-κB. GRO-α 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-α-Snail axis in NMIBC represents a promising alternative to prevent post-therapeutic tumor progression and recurrence.
Oncotarget. 2017 Apr 03 [Epub ahead of print]
Lu Chen, Xiu-Wu Pan, Hai Huang, Yi Gao, Qi-Wei Yang, Lin-Hui Wang, Xin-Gang Cui, Dan-Feng Xu
Department of Urinary Surgery of Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China., Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai 201805, China., Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.