5-aza-2 '-deoxycitidine inhibits cell proliferation, extracellular matrix formation and Wnt/beta-catenin pathway in human uterine leiomyomas

Data de publicació: 08/07/2021 Data Ahead of Print: 08/07/2021

Autors de IIS La Fe

Maria Cristina Carbajo García

Autor
Ana Corachán García

Autor
Marina Segura

Autor
Javier Monleón Sancho

Autor
Julia Escrig Estrems

Autor
Amparo Faus Esteve

Autor
Antonio Pellicer Martínez

Autor
Irene Cervelló Alcaraz

Autor
Hortensia Ferrero Chafer

Autor

Grups d'Investigació

Biología Reproductiva y Bioingeniería en Reproducción Humana

Leader

Nicolás Garrido Puchalt
Medicina Reproductiva

Investigador Principal

José Morales Roselló

Abstract

Background: Uterine leiomyoma is a benign tumor with unclear pathogenesis and inaccurate treatment. This tumor exhibits altered DNA methylation related to disease progression. DNMT inhibitors as 5-aza-2'-deoxycytidine (5-aza-CdR), have been suggested to treat tumors in which DNA methylation is altered. We aimed to evaluate whether DNA methylation reversion with 5-aza-CdR reduces cell proliferation and extracellular matrix (ECM) formation in uterine leiomyoma cells to provide a potential treatment option. Methods: Prospective study using uterine leiomyoma and adjacent myometrium tissues and human uterine leiomyoma primary (HULP) cells (n = 16). In tissues, gene expression was analyzed by qRT-PCR and DNMT activity by ELISA. Effects of 5-aza-CdR treatment on HULP cells were assessed by CellTiter, western blot, and qRT-PCR. Results: DNMT1 gene expression was higher in uterine leiomyoma vs myometrium. Similarly, DNMT activity was greater in uterine leiomyoma and HULP cells (6.5 vs 3.8 OD/h/mg; 211.3 vs 63.7 OD/h/mg, respectively). After 5-azaCdR treatment on HULP cells, cell viability was reduced, significantly so at 10 mu M (85.3%). Treatment with 10 mu M 5-aza-CdR on HULP cells significantly decreased expression of proliferation marker PCNA (FC = 0.695) and of ECM proteins (COLLAGEN I FC = 0.654; PAI-1, FC = 0.654; FIBRONECTIN FC = 0.733). 5-aza-CdR treatment also decreased expression of Wnt/beta-catenin pathway final targets, including WISP1 protein expression (10 pM, FC = 0.699), c-MYC gene expression (2 mu M, FC = 0.745 and 10 mu M, FC = 0.728), and MMP7 gene expression (5 mu M, FC = 0.520 and 10 mu M, FC = 0.577). Conclusions: 5-aza-CdR treatment inhibits cell proliferation, ECM formation, and Wnt/beta-catenin signaling pathway targets in HULP cells, suggesting that DNA methylation inhibition is a viable therapeutic target in uterine leiomyoma.

Dades de la publicació

ISSN/ISSNe:: 1477-7827, 1477-7827
Tipus:: Article
Pàgines:: 106-106
DOI:: 10.1186/s12958-021-00790-5
PubMed:: 34233687
Factor d'Impacte:: 1,198 SCImago ℠
Quartil:: Q1 SCImago ℠

Documents

No hi ha documents

Mètriques

Filiacions

Carbajo-García MC:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

2 Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain.
Corachán A:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

2 Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain.
Segura-Benitez M:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

2 Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain.
Monleón J:: 3 Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Escrig J:: 3 Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Faus A:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.
Pellicer A:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

4 IVIRMA Rome, Rome, Italy.
Cervelló I:: Instituto de Investigación. 1 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

#Contributed equally.
Ferrero H:: Instituto de Investigación. 5 Fundación IVI, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Spain.

#Contributed equally.