Quercetin shortened survival of radio-resistant B-1 cells in vitro and in vivo by restoring miR15a/16 expression
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Yasmim Alefe Leuzzi Ramos1, Olivia Fonseca Souza1, Marilia Campos Tavares Novo1, Caroline Ferreira Cunha Guimarães1 and Ana Flavia Popi1
1 Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
|Ana Flavia Popi,||email:||[email protected]|
Keywords: B-1 cells; chronic lymphocytic leukemia; quercetin; Wnt; miRNA
Abbreviations: CLL: Chronic lymphocytic leukemia; NZB/W: New Zealand Black/White mice; NOD/SCID: Nonobese diabetic/severe combined immunodeficiency mice; GFP: green fluorescence protein
Received: December 11, 2019 Accepted: September 10, 2020 Published: February 16, 2021
Chronic lymphocytic leukemia (CLL) is a malignancy disease characterized by the expansion of CD5+ B-1 cells. The NZB mouse model of CLL shows similarities to human CLL, has age-associated increase in malignant B-1 clones and decreased expression of miR-15a/16. It was demonstrated that systemic lentiviral delivery of miR-15a/16 ameliorates disease manifestations in this mouse model. Nowadays, new therapeutic approaches have been focus on miRNA in cancer cells. Natural compounds like quercetin can modulate these miRNAs, consequently, suppress oncogenes or stimulate tumor suppressor genes by altering miRNA expressions. Here we investigate the effects of quercetin on miRNA15a/16 expression by radio-resistant B-1 cells. It has been described that a small percentage of B-1 cell survives to irradiation in vitro, and these cells show similarities to B-CLL cells. In these cells, the level of miR15a/16 is diminished and Bcl-2 is overexpressed. Quercetin treatment restore both, miR15a/16 and Bcl-2, to normal levels. Furthermore, transference of radioresistant B-1 cells to NOD/SCID mice causes an expansion of this population and also a migration to the liver. However, after quercetin treatment, even radioresistant B-1 cells are not able to expand or disseminate in vivo, and the levels of miR15a/16 and Bcl-2 are also normalized. Our data support the hypothesis that quercetin is an important adjuvant molecule that acts on miRNA15a/16 level and leads cells more permissive to apoptosis. This work could help to design new approaches to therapy in CLL patients.
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