Relevance of iNOS expression in tumor growth and maintenance of cancer stem cells in a bladder cancer model.

DENISE BELGOROSKY; ; JULIE GIROUARD, ; YANINA VERONICA LANGLE, ; JOVANE HAMELIN-MORRISSETE; ; LINA MARINO; ; EDUARDO IMANOL AGÜERO; ; HÉCTOR MALAGRINO, ; CARLOS REYES-MORENO, ; ANA MARÍA EIJÁN,

JOURNAL OF MOLECULAR MEDICINE (BERLIN, GERMANY)

SPRINGER

Lugar: Berlin; Año: 2020

0946-2716

Purpose : The expression of inducible nitric oxide (NO) synthase (iNOS) in humanbladder cancer (BC) is a poor prognostic factor associated with invasion and tumorrecurrence. Here, we evaluated the relevance of iNOS expression in BC progressionand in cancer stem cell (CSC) maintenance in a murine BC model. Also, iNOSexpression and CSC markers were analyzed in human BC samples.Methods: iNOS inhibitors (L-NAME or 1400W) or shRNA were used on murine BC model with different iNOS expression and invasiveness grade: MB49 (iNOS+, nonmuscle invasive (NMI)) and MB49-I (iNOS++, muscle invasive (MI)), in order to analyzed cell proliferation, tumor growth, angiogenesis, number of CSC, and pluripotential markers expression. iNOS, SOX2, Oct4 and Nanog expression were also analyzed in human BC samples by qPCR and immunohistochemistry.Results : iNOS inhibition reduced cell proliferation, tumor growth, angiogenesis, andthe number of CSC. The number of CSCs, generated by MB49-I resulted higher thanMB49, in concordance with the higher expression of SOX2, Oct4 and Nanog. Theexpression of SOX2 was notoriously diminished, when iNOS was inhibited only in theMI cell line. Similar results were observed in human samples, where, MI tumorsexpressed higher levels of iNOS and pluripotential genes, in comparison to NMI tumorswith a positive correlation between those and iNOS, suggesting that iNOS expressionis associated with CSC. Conclusion: iNOS plays an important role in BC progression and CSC maintenance.Its inhibition could be a potential therapeutic target to eradicate CSC, responsible oftumor recurrences.