Abstract
BackgroundThe glycosylphosphatidylinositol (GPI)-anchored epithelial extracellular membrane serine protease prostasin (PRSS8) is expressed abundantly in normal epithelia and essential for terminal epithelial differentiation, but down-regulated in human prostate, breast, and gastric cancers and invasive cancer cell lines. Prostasin is involved in the extracellular proteolytic modulation of the epidermal growth factor receptor (EGFR) and is an invasion suppressor. The aim of this study was to evaluate prostasin expression states in the transitional cell carcinomas (TCC) of the human bladder and in human TCC cell lines.MethodsNormal human bladder tissues and TCC on a bladder cancer tissue microarray (TMA) were evaluated for prostasin expression by means of immunohistochemistry. A panel of 16 urothelial and TCC cell lines were evaluated for prostasin and E-cadherin expression by western blot and quantitative PCR, and for prostasin gene promoter region CpG methylation by methylation-specific PCR (MSP).ResultsProstasin is expressed in the normal human urothelium and in a normal human urothelial cell line, but is significantly down-regulated in high-grade TCC and lost in 9 (of 15) TCC cell lines. Loss of prostasin expression in the TCC cell lines correlated with loss of or reduced E-cadherin expression, loss of epithelial morphology, and promoter DNA hypermethylation. Prostasin expression could be reactivated by demethylation or inhibition of histone deacetylase. Re-expression of prostasin or a serine protease-inactive variant resulted in transcriptional up-regulation of E-cadherin.ConclusionLoss of prostasin expression in bladder transitional cell carcinomas is associated with epithelial-mesenchymal transition (EMT), and may have functional implications in tumor invasion and resistance to chemotherapy.
Highlights
The glycosylphosphatidylinositol (GPI)-anchored epithelial extracellular membrane serine protease prostasin (PRSS8) is expressed abundantly in normal epithelia and essential for terminal epithelial differentiation, but down-regulated in human prostate, breast, and gastric cancers and invasive cancer cell lines
We have shown that a glycosylphosphatidylinositol (GPI)-anchored epithelial extracellular membrane serine protease, prostasin/PRSS8, modulates epidermal growth factor receptor (EGFR) signalling via enhancement of matriptase cleavage of the EGFR extracellular domain (ECD), and regulates SLUG and E-cadherin expression in cancer cells [7,8]
Prostasin protein is expressed in the normal urothelial cell line UROtsa, and in transitional cell carcinomas (TCC) cell lines with epithelial morphology but not mesenchymal morphology We further evaluated prostasin protein expression in a panel of urothelial cell lines, including a normal immortalized urothelial cell line UROtsa, and TCC cell lines HT1376, J82, RT4, T24, KU-7, 253J P, 253J B-V, UM-UC-3, 5, -6, -9, -10, -12, -13, and -14
Summary
The glycosylphosphatidylinositol (GPI)-anchored epithelial extracellular membrane serine protease prostasin (PRSS8) is expressed abundantly in normal epithelia and essential for terminal epithelial differentiation, but down-regulated in human prostate, breast, and gastric cancers and invasive cancer cell lines. The aim of this study was to evaluate prostasin expression states in the transitional cell carcinomas (TCC) of the human bladder and in human TCC cell lines. For bladder cancer patients of all stages, the 5-year survival rate is 80%. The 5-year survival rate sharply declines to 45% and 6% for patients with regional and distant metastasis, respectively. The remaining bladder cancer cases (20-30%) are non-papillary invasive tumors that produce lymphatic and distant metastasis, accounting for most of the bladder cancer deaths. Radical cystectomy combined with chemo- or radiation therapy is required for patients with invasive bladder cancers, and offers improved survival [3]. I.e., invasive tumors that escaped the current chemo- or radiation adjuvant therapy, new drugs and new drug targets are needed
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