La serino-proteasi linfocitaria Granzyme B è espressa nei carcinomi della vescica e svolge un ruolo nell'invasione tumorale
Author(s)
D'Eliseo, Donatella
Date Issued
March 16, 2010
Type
Doctoral Thesis
Abstract
Granzyme B (GrB) is a serine proteinase known to be expressed by cytotoxic lymphocytes (T
lymphocytes and NK cells) and to induce, in presence of perforin (Pf), apoptosis in target cells, such us infected and tumor cells. Recently, GrB expression has been also 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 bladder cancer tissues by RT-PCR, Western blot, ELISA, immunofluorescence, and immunohistochemistry.
- GrB function of in bladder cancer cell lines; the in vitro function of GrB was examined by lossof- 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 (EMT), a key event in carcinoma invasion. Indeed, GrB-positive cells also expressed Snail, N-cadherin, or were negative for E-cadherin. Tumor-expressed GrB 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.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
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