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Mol Oncol. 2016 Aug;10(7):1043-53. doi: 10.1016/j.molonc.2016.04.004. Epub 2016 Apr 23.

miR-200c and phospho-AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis.

Author information

1
Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Spain; Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, Spain.
2
Laboratory of Cellular and Molecular Biology, Instituto de Investigación Sanitaria La Fe, Spain.
3
Genomics Unit, Instituto de Investigación Sanitaria La Fe, Spain.
4
Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Spain.
5
Department of Pathology, Hospital La Fe, Spain.
6
Department of Pathology, Instituto Valenciano de Oncología, Spain.
7
Department of Pathology, University of Valencia, Spain.
8
Clinical and Translational Research in Cancer, Instituto de Investigación Sanitaria La Fe, Spain; Laboratory of Cellular and Molecular Biology, Instituto de Investigación Sanitaria La Fe, Spain. Electronic address: jaime.fontdemora@gmail.com.

Abstract

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.

KEYWORDS:

Lung metastasis; Mesenchymal to epithelial transition; Pediatric osteosarcoma; Phospho-AKT; miR-200c

PMID:
27155790
PMCID:
PMC5423177
DOI:
10.1016/j.molonc.2016.04.004
[Indexed for MEDLINE]
Free PMC Article

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