Abstract
Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 μg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1β and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment.
MeSH terms
-
Animals
-
Cell Line, Tumor
-
Cell Movement / drug effects
-
Cell Movement / genetics
-
Cell Proliferation / drug effects
-
Cytokines / metabolism
-
Dexamethasone / pharmacology
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Down-Regulation / drug effects
-
Down-Regulation / genetics
-
Female
-
Gene Expression Regulation, Neoplastic / drug effects
-
Glucocorticoids / pharmacology*
-
Glucocorticoids / therapeutic use
-
Immunocompetence / drug effects*
-
Inflammation Mediators / metabolism
-
Macrophages / drug effects
-
Macrophages / metabolism
-
Macrophages / pathology
-
Mice, Inbred C57BL
-
MicroRNAs / genetics
-
MicroRNAs / metabolism
-
Models, Biological
-
Myeloid-Derived Suppressor Cells / metabolism
-
Myeloid-Derived Suppressor Cells / pathology
-
Neoplasm Invasiveness
-
Neoplasm Metastasis
-
Ovarian Neoplasms / drug therapy
-
Ovarian Neoplasms / genetics
-
Ovarian Neoplasms / pathology*
-
Signal Transduction / drug effects
-
Transcription, Genetic / drug effects
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
-
rap GTP-Binding Proteins / genetics
-
rap GTP-Binding Proteins / metabolism
Substances
-
Cytokines
-
Glucocorticoids
-
Inflammation Mediators
-
MicroRNAs
-
Dexamethasone
-
Rap1b protein, mouse
-
rap GTP-Binding Proteins
Grants and funding
This study was supported by 105A1-MGPP11-014 from National Research Health Institutes, MOST-104-2320-B-400-011-MY3 and MOST-105-2321-B-400 -012 -MY3 from the Ministry of Science and Technology, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.