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

Oncotarget. 2017 Jul 11;8(28):45274-45285. doi: 10.18632/oncotarget.16786.

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.

Keywords: CXCR2; GRO-α; bladder cancer; epithelial-mesenchymal transition; recurrence.

MeSH terms

  • Administration, Intravesical
  • Animals
  • Chemokine CXCL1 / metabolism*
  • Epirubicin / administration & dosage
  • Epithelial-Mesenchymal Transition
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / pathology
  • Random Allocation
  • Receptors, Interleukin-8B / metabolism*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • CXCL1 protein, human
  • Chemokine CXCL1
  • Receptors, Interleukin-8B
  • Epirubicin