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.
Highlights
75–85% cases of newly diagnosed bladder cancer are non-muscle invasive bladder cancer (NMIBC), including non-muscle invasive papillary or flat lesions and invasive urothelial carcinomas involving the lamina propria [1]
These data suggest that recurrent bladder cancer cells underwent epithelial-mesenchymal transition accompanied with malignant progression
To gain deeper insights into the regulatory effect of GRO-α-CXCR2 signaling on Snail functions, we examined the effect of GRO-α upon the subcellular localization of Snail in bladder cancer cells by scanning confocal microscopy
Summary
75–85% cases of newly diagnosed bladder cancer are non-muscle invasive bladder cancer (NMIBC), including non-muscle invasive papillary or flat lesions (pTa and pTis, respectively) and invasive urothelial carcinomas involving the lamina propria (pT1) [1]. Tumor cells progress from non-invasive to malignant phenotypes via a series of critical steps that involve morphological changes referred to as the epithelial– mesenchymal transition (EMT). Downregulation of epithelial markers was associated with disease progression in terms of both grade and stage (i.e., superficial vs muscle-invasive cancer), and in univariate analyses, downregulation of either β-catenin or plakoglobin was associated with shorter disease-specific www.impactjournals.com/oncotarget survival [8]. Kajiyama et al identified an association between chronic paclitaxel resistance and induction of EMT in epithelial ovarian carcinomas [10]. Based on these observations, we hypothesize that EMT may contribute to the malignant phenotypes of bladder cancers after receiving chemotherapy
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