RT info:eu-repo/semantics/article
T1 miR-200c and phospho-AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis
A1 Berlanga, Pablo
A1 Muñoz-Hidalgo, Lisandra
A1 Piqueras, Marta
A1 Sirerol, J. Antoni
A1 Sánchez-Izquierdo, María Dolors
A1 Hervás Marín, David
A1 Llavador, Margarita
A1 Machado, Isidro
A1 Llombart Bosch, Antonio
A1 Cañete, Adela
A1 Castel, Victoria
A1 Font de Mora, Jaime
K1 Pediatric osteosarcoma
K1 miR-200c
K1 Mesenchymal to epithelial transition
K1 Phospho-AKT
K1 Lung metastasis
AB Lung metastasis is the major cause of death in osteosarcoma patients. However, molecular mechanisms underlying this metastasis remain poorly understood. To identify key molecules related with pulmonary metastasis of pediatric osteosarcomas, we analyzed high-throughput miRNA expression in a cohort of 11 primary tumors and 15 lung metastases. Results were further validated with an independent cohort of 10 primary tumors and 6 metastases. In parallel, we performed immunohistochemical analysis of activated signaling pathways in 36 primary osteosarcomas. Only phospho-AKT associated with lower overall survival in primary tumors, supporting its role in osteosarcoma progression. CTNNB1 expression also associated with lower overall survival but was not strong enough to be considered an independent variable. Interestingly, miR-200c was overexpressed in lung metastases, implicating an inhibitory feed-back loop to PI3K-AKT. Moreover, transfection of miR200c-mimic in U2-OS cells reduced phospho-AKT levels but increased cellular migration and proliferation. Notably, miR-200c expression strongly correlated with miR-141 and with the osteogenic inhibitor miR-375, all implicated in epithelial to mesenchymal transition. These findings contrast epithelial tumors where reduced miR-200c expression promotes metastasis. Indeed, we noted that osteosarcoma cells in the lung also expressed the epithelial marker CDH1, revealing a change in their mesenchymal phenotype. We propose that miR-200c upregulation occurs late in osteosarcoma progression to provide cells with an epithelial phenotype that facilitates their integration in the metastatic lung niche. Thus, our findings identify phospho-AKT in the primary tumor and miR-200c later during tumor progression as prognostic molecules and potential therapeutic targets to prevent progression and metastasis of pediatric osteosarcomas.
SN 1574-7891
YR 2016
FD 2016
LK http://riull.ull.es/xmlui/handle/915/36165
UL http://riull.ull.es/xmlui/handle/915/36165
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 18-sep-2024