MicroRNA-16 suppresses metastasis in an orthotopic, but not autochthonous, mouse model of soft tissue sarcoma

MicroRNAs (miRNAs) can regulate tumor cell invasion and metastasis in a tumor-specific manner. We recently demonstrated that global downregulation of miRNAs after deleting dicer can promote development of distant metastases in a mouse model of primary soft tissue sarcoma (STS). In this study, we ide...

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Published in:	Disease models & mechanisms Vol. 8; no. 8; pp. 867 - 875
Main Authors:	Sachdeva, Mohit, Whitley, Melody J, Mito, Jeffrey K, Ma, Yan, Lev, Dina C, Cardona, Diana M, Kirsch, David G
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Ltd 01-08-2015 The Company of Biologists
Subjects:	Animals Cancer Cell cycle Cell growth Cell Line, Tumor Cell Movement - genetics Disease Models, Animal Down-Regulation - genetics Gene Deletion Gene Expression Regulation, Neoplastic Genetic engineering Humans Lungs Metastasis Mice, Nude MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Mortality Mouse models Mutation Neoplasm Invasiveness Neoplasm Metastasis RNA polymerase Sarcoma Sarcoma - genetics Sarcoma - pathology Soft tissue sarcoma Tumors Soft tissue sarcoma Genetic engineering MicroRNA Metastasis Mouse models
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Summary:	MicroRNAs (miRNAs) can regulate tumor cell invasion and metastasis in a tumor-specific manner. We recently demonstrated that global downregulation of miRNAs after deleting dicer can promote development of distant metastases in a mouse model of primary soft tissue sarcoma (STS). In this study, we identified miRNAs that are differentially downregulated in metastatic STS in both human and mouse, and investigated the role of these miRNAs in metastasis. miRNA- TaqMan PCR arrays showed a global downregulation of miRNAs in metastatic human sarcomas. Similar analysis in mouse metastatic sarcomas revealed overlap for several downregulated miRNAs including miR-16, miR-103, miR-146a, miR-223, miR-342 and miR-511. Restoration of these downregulated miRNAs in mouse primary sarcoma cell lines showed that miR-16, but not other downregulated miRNAs, was able to significantly suppress both migration and invasion in vitro, without altering cell proliferation. In addition, orthotopic transplantation of a sarcoma cell line stably expressing miR-16 into the muscle of immunocompromised mice revealed that restoration of miR-16 can significantly decrease lung metastasis in vivo. However, no change in the rate of lung metastasis was observed when miR-16 was deleted in mouse primary sarcomas at sarcoma initiation. Taken together, these results indicate that miR-16 can have metastasis-suppressing properties both in vitro and in vivo. However, the loss-of-function experiments in autochthonous tumors indicate that loss of miR-16 is not sufficient to promote metastasis in vivo.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
ISSN:	1754-8403 1754-8411 1754-8411 1754-8403
DOI:	10.1242/dmm.017897