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

// Lu Chen 1, * , Xiu-Wu Pan 2, 3, * , Hai Huang 3, * , Yi Gao 3 , Qi-Wei Yang 2, 3 , Lin-Hui Wang 3 , Xin-Gang Cui 2 and Dan-Feng Xu 1 1 Department of Urinary Surgery of Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China 2 Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai 201805, China 3 Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, Shanghai 200003, China * These authors have contributed equally to this work Correspondence to: Xin-Gang Cui, email: xingangcui@126.com Dan-Feng Xu, email: nycnjc@126.com Keywords: GRO-α, CXCR2, bladder cancer, epithelial-mesenchymal transition, recurrence Received: March 24, 2016      Accepted: March 17, 2017      Published: April 03, 2017 ABSTRACT 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.