Abstract
Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Here we reveal a novel role for glucocorticoids in the inhibition of ovarian cancer metastasis. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrin-mediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Clinically, low miR-708 and high Rap1B are found in late-state ovarian tumours, as compared with normal, and patients with high miR-708 show significantly better survival. Overall, our findings reveal an opportunity for glucocorticoids and their downstream mediators, miR-708 or Rap1B, as therapeutic modalities against metastatic ovarian epithelial cancer.
Highlights
Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions
MiRNA-708 is downregulated in metastatic ovarian cancer
Expression of miR-708 resulted in a significant inhibition of cell migration/invasion in transwell assay among all ovarian cancer lines tested (Fig. 1e), Figure 1 | MiR-708 acts as ovarian cancer metastasis suppressor. (a) Heatmap of 21 most differentially regulated miRNAs from miRNA array of SKOV (Right) and SKOV-I6iv (Left). (b,c) Expression of miR-708 in ovarian tumours by FISH analysis of commercial tissue arrays
Summary
Glucocorticoids are widely used in conjunction with chemotherapy for ovarian cancer to prevent hypersensitivity reactions. Glucocorticoid treatments induce the expression of miR-708, leading to the suppression of Rap1B, which result in the reduction of integrinmediated focal adhesion formation, inhibition of ovarian cancer cell migration/invasion and impaired abdominal metastasis in an orthotopic xenograft mouse model. Restoring Rap1B expression reverts glucocorticoid-miR-708 cascade-mediated suppression of ovarian cancer cell invasion and metastasis. Expression of miR-708 impaired breast cancer metastasis via modulation of neuronatin[14] Despite these advances recognizing miR-708 as a potential tumour suppressor, its role in ovarian cancer has not been reported and the detailed mechanism of how miR-708 is under regulation remains elusive. We report the finding that GC treatments play a suppressive role in ovarian cancer metastasis via the induction of miR-708. Our study reveals a potential role and underlying mechanism of GCs in the suppression of ovarian cancer metastasis
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