Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma
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The Ohio State University / OhioLINK
2015
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu14297619232021-08-03T06:30:31Z Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma Fenger, Joelle M. Molecular Biology microRNA miR-9 mast cell tumor osteosarcoma comparative oncology canine MicroRNAs (miRNAs) are small, non-coding RNAs that serve as important regulators of gene expression. While miRNA expression is known to be altered in a variety of human malignancies contributing to cancer development and progression, there are limited data regarding the potential role of miRNA dysregulation in spontaneous canine malignancies. The purpose of this dissertation was to investigate the potential contribution of miRNA dysregulation to the biology of canine mast cell tumors (MCTs) and canine osteosarcoma (OSA), two well-established large animal models of spontaneous malignant disease. We first evaluated miRNA expression profiles in biologically low grade and biologically high grade, metastatic primary canine MCTs and demonstrated that unique miRNA expression profiles correlate with biological behavior. Furthermore, we identified miR-9 as being significantly overexpressed in aggressive primary MCTs and malignant canine mastocytoma cell lines compared to benign MCTs and normal canine bone marrow-derived mast cells (BMMCs). We found that enforced miR-9 expression in murine mastocytoma cell lines and normal murine BMMCs with low basal levels of miR-9 enhanced invasion and induced the expression of several target genes associated with metastasis, suggesting that miR-9 overexpression may contribute to the invasive phenotype of malignant mast cells in vitro and the development of metastasis in canine MCTs in vivo. We subsequently evaluated miRNA expression in primary canine OSA tumors and normal canine osteoblasts and found that a unique miRNA expression signature is associated with spontaneously occurring canine OSA. We found that similar to human OSA tumors, miR-9 expression is increased in primary canine OSA tumor specimens and OSA cell lines compared to normal canine osteoblasts and primary osteoblast cultures, supporting the idea that dysregulation of miR-9 may be fundamental to the disease process in both species. Our data indicate that miR-9 contributes to the aggressive biologic behavior of OSA, possibly through the promotion of a metastatic phenotype as demonstrated by enhanced invasion and migration in normal osteoblasts and OSA cell lines and alteration of gene and protein expression profiles associated with cellular invasion in the presence of enforced miR-9 expression. Manipulation of miR-9 expression in normal osteoblasts and OSA cell lines altered the expression of the actin filament-severing protein gelsolin, supporting the notion that miR-9 may contribute to the invasive and metastatic nature of OSA, in part, through upregulation of gelsolin expression. Finally, we generated a mast cell-specific cre-inducible transgenic mouse model to better characterize the molecular mechanisms through which miR-9 regulates the expression of factors responsible for mast cell invasion in vitro, and to study the role of miR-9 in normal mast cell biology in vivo. In summary, these studies provide significant new data regarding the role of miRNA dysregulation in canine MCT and OSA biology by characterizing tumor-specific miRNA expression profiles associated with aggressive biological behavior, identifying dysregulation of miR-9 in contributing to the metastatic phenotype, and providing a novel transgenic mouse model to investigate the biological role of miR-9 in vivo. 2015-05-20 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1429761923 http://rave.ohiolink.edu/etdc/view?acc_num=osu1429761923 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Molecular Biology microRNA miR-9 mast cell tumor osteosarcoma comparative oncology canine |
| spellingShingle |
Molecular Biology microRNA miR-9 mast cell tumor osteosarcoma comparative oncology canine Fenger, Joelle M. Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| author |
Fenger, Joelle M. |
| author_facet |
Fenger, Joelle M. |
| author_sort |
Fenger, Joelle M. |
| title |
Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| title_short |
Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| title_full |
Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| title_fullStr |
Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| title_full_unstemmed |
Investigating the Biological and Molecular Consequences of MiR-9 Dysregulation in Canine Mast Cell Tumors and Osteosarcoma |
| title_sort |
investigating the biological and molecular consequences of mir-9 dysregulation in canine mast cell tumors and osteosarcoma |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2015 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429761923 |
| work_keys_str_mv |
AT fengerjoellem investigatingthebiologicalandmolecularconsequencesofmir9dysregulationincaninemastcelltumorsandosteosarcoma |
| _version_ |
1719438149809078272 |