Granzyme B is expressed in urothelial carcinoma and promotes cancer cell invasion

Donatella D'Eliseo, Paola Pisu, Chiara Romano, Andrea Tubaro, Cosimo De Nunzio, Stefania Morrone, Angela Santoni, Antonella Stoppacciaro, Francesca Velotti

Research output: Contribution to journalArticlepeer-review

Abstract

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 nonlymphoid cells, but its function is not defined. In our study, we investigated GrB and Pf expression in bladder cancer cell lines and in urothelial carcinoma (UC) tissues by reverse transcription-polymerase chain reaction (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 markedly 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.

Original languageEnglish
Pages (from-to)1283-1294
Number of pages12
JournalInternational Journal of Cancer
Volume127
Issue number6
DOIs
Publication statusPublished - Sep 1 2010

Keywords

  • Epithelial-mesenchymal transition
  • Extracellular matrix
  • Granzyme B
  • Invasion
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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