Abstract
Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.
Highlights
Published: 15 March 2021Recent advances in molecular characterization have identified several subtypes of urothelial carcinoma of the bladder (UCB), with implications for prognosis and response to therapy [1,2,3]
We investigated the impact of Grainyhead-like 3 (GRHL3) in the proliferation, migration and invasion of urothelial cells by gain- and loss-of-function assays in bladder cancer cell lines
In order to understand the contribution of GRHL3 in bladder cancer cells, we determined its mRNA levels in three bladder cancer cell lines by semi-quantitative Reverse Transcription (RT)-Polymerase Chain Reaction (PCR)
Summary
Published: 15 March 2021Recent advances in molecular characterization have identified several subtypes of urothelial carcinoma of the bladder (UCB), with implications for prognosis and response to therapy [1,2,3]. Basal/squamous-type UCBs are characterized by a loss of terminal urothelial differentiation markers and show a more aggressive phenotype with worse oncological outcomes compared to luminal subtypes expressing differentiationassociated markers, such as peroxisome proliferator-activated receptor gamma (PPARγ), forkhead box protein A1 (FOXA1) and cytokeratin 20 [1,2,5]. The transcription factor Grainyhead-like 3 (GRHL3) holds an important role in the establishment of a urothelial phenotype in the developing mouse bladder and is mainly expressed in luminal, terminally differentiated umbrella cells [6,7]. Serial transcriptome analysis by gene arrays identified a group of transcription factors such as PPARγ, FOXA1, E74 Like ETS Transcription Factor 3 (ELF3)
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