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Title: Granzyme B is expressed in urothelial carcinoma and promotes cancer cell invasion
Authors: D'Eliseo, Donatella
Pisu, Paola
Romano, Chiara
Tubaro, Andrea
De Nunzio, Cosimo
Morrone, Stefania
Santoni, Angela
Stoppacciaro, Antonella
Velotti, Francesca Romana
Keywords: Tumor invasion;Granzyme B;Urothelial carcinoma
Issue Date: 2010
Publisher: Wiley-Blackwell
Source: D'Eliseo, D. et al. 2010. Granzyme B is expressed in urothelial carcinoma and promotes cancer cell invasion. "International Journal of Cancer" 127 (6): 1283-1294
Granzyme B (GrB) is a serine proteinase known to be expressed by cytotoxic lymphocytes and to induce, in presence of perforin (Pf), apoptosis in target cells. Recently, GrB expression has been shown (often in absence of Pf) in non-lymphoid cells, but its function is not defined. In this study, we investigated GrB and Pf expression in bladder cancer cell lines and in urothelial carcinoma (UC) tissues by RT-PCR, Western blot, ELISA, immunofluorescence, and immunohistochemistry. We also assessed the function of GrB in UC cells; the in vitro function of GrB was examined by loss-of-function experiments. Our results revealed that GrB is expressed, in absence of Pf, in UC cells. Significant differences were found between GrB expression and both increasing pathological tumor spreading and high grade vs low grade pTa tumors. Notably, GrB in UC tissues was concentrated at the cancer invasion front and was expressed in neoplastic cells undergoing epithelial-mesenchymal transition, a key event in carcinoma invasion. Indeed, GrB-positive cells also expressed Snail, N-cadherin, or were negative for E-cadherin. GrB expressed in tumor cell lines was enzymatically active and capable of vitronectin cleavage, implying extracellular matrix (ECM) remodeling by GrB. Inhibition of GrB activity or Stealth RNA interference-mediated GrB gene silencing dramatically suppressed bladder cancer cell invasion through matrigel. This data provides the first evidence for a role of GrB in promoting cancer cell invasion. Taken together, our findings suggest that GrB, via ECM degradation, contributes to the establishment of the UC invasive phenotype.
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ISSN: 0020-7136
DOI: 10.1002/ijc.25135
Appears in Collections:DECOS - Archivio della produzione scientifica

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