miR-409-3p/-5p promotes tumorigenesis, epithelial to mesenchymal transition and bone metastasis of human prostate cancer
Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence le rôle joué par le micro-ARN miR-409-3p/-5p dans la croissance tumorale, la transition épithélio-mésenchymateuse et la formation de métastases osseuses
Purpose: miR-409-3p/-5p is a microRNA expressed by embryonic stem cells and its role in cancer biology and metastasis is unknown. Our pilot studies demonstrated elevated miR-409-3p/-5p expression in human prostate cancer bone metastatic cell lines, therefore we defined the biological impact of manipulation of miR-409-3p/-5p in prostate cancer progression and correlated the levels of its expression with clinical human prostate cancer bone metastatic specimens. Experimental Design: miRNA profiling of prostate cancer bone metastatic EMT cell line model was performed. Gleason score human tissue array was probed for validation of specific miRNAs. Additionally, genetic manipulation of miR-409-3p/-5p was performed to determine its role in tumor growth, epithelial to mesenchymal transition (EMT) and bone metastasis in mouse models. Results: Elevated expression of miR-409-3p/-5p was observed in bone metastatic prostate cancer cell lines and human prostate cancer tissues with higher Gleason scores. Elevated miR-409-3p expression levels correlated with prostate cancer patient progression free survival. Orthotopic delivery of miR-409-3p/-5p in the murine prostate gland induced tumors where the tumors expressed, EMT and stemness markers. Intracardiac inoculation (to mimic systemic dissemination) of miR-409-5p inhibitor treated bone metastatic ARCaPM prostate cancer cells in mice, led to decreased bone metastasis and increased survival compared to control vehicle-treated cells. Conclusion: miR-409-3p/-5p plays an important role in prostate cancer biology by facilitating tumor growth, EMT and bone metastasis. This finding bear's particular translational importance since miR-409-3p/-5p appears to be an attractive biomarker and/or possibly a therapeutic target to treat bones metastatic prostate cancer.