Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low-and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1a (HIF-1a), and overexpression of SOX4 and HIF-1a effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1a by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138 low / SOX high signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1a pathways.Metastatic ovarian cancer is the deadliest among gynecologic malignancies, with an estimated 15,500 deaths in the United States in 2012, as reported by the National Cancer Institute. The overall 5-year survival rate is 33% when diagnosed at advanced stages; it is about 90% while the cancer is still confined to the ovary (stage I). 1 At late stages, tumor cells spread beyond the pelvic cavity and commonly undergo metastasis to the mesentery, omentum and diaphragm. 2 Metastasis to the pelvic and para-aortic lymph nodes may also occur. Elucidating the mechanisms underlying cancer metastasis will, thus, make significant contributions toward combating this disease. MicroRNAs (miRNAs), a family of small noncoding single-stranded RNAs, have recently been shown to play essential roles in cancer cell invasion and metastasis. 3 One miRNA can suppress multiple gene expressions by interacting with the 3 0 nontranslated regions (3 0 UTRs) of its target mRNAs and promoting their degradation or translational suppression resulting in the modulation of those genes' expressions and functions.A couple of recent studies have reported the role of miRNAs in modulating ovarian cancer cell invasion and metastasis. Cowden Dahl et al. showed that epidermal growth factor receptor (EGFR)-responsive miR-125a induced a mesenchymalto-epithelial transition (MET) in ovarian cancer cells. MiR125a directly targets ARID3B, which is overexpressed in serous ovarian cancer. 4 Corney et al. reported that p53-transactivated miR-34 was decreased in metastatic ovarian cance...

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.

Purpose: Because the combination of multiple modalities for cancer treatment is more likely to generate more potent therapeutic effects for the control of cancer, we have explored the combination of chemotherapy using cisplatin, which is routinely used in chemotherapy for advanced cervical cancer, with immunotherapy using DNA vaccines encoding calreticulin (CRT) linked to human papillomavirus type 16 E7 antigen (CRT/E7) in a preclinical model. Experimental Design: We characterized the combination of cisplatin with CRT/E7 DNA vaccine using different regimen for its potential ability to generate E7-specific CD8 + T-cell immune responses as well as antitumor effects against E7-expressing tumors. Results: Our results indicate that treatment of tumor-bearing mice with chemoimmunotherapy combining cisplatin followed by CRT/E7 DNA generated the highest E7-specific CD8 + T-cell immune response and produced the greatest antitumor effects and long-term survival as well as significant levels of E7-specific tumor-infiltrating lymphocytes compared with all the other treatment regimens. Furthermore, we found that treatment with cisplatin leads to the cellmediated lysis of E7-expressing tumor cells in vitro and increased number of E7-specific CD8 + T-cell precursors in tumor-bearing mice. In addition, we observed that E7-specific CD8 + T cells migrate to and proliferate in the location of TC-1tumors in mice treated with cisplatin. Conclusions: Thus, our data suggest that chemoimmunotherapy using cisplatin followed by CRT/E7 DNA vaccine is an effective treatment against E7-expressing tumors and may potentially be translated into the clinical arena.Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer (see refs. 1, 2 for reviews). Antigen-specific immunotherapy is an attractive approach for the treatment of cancers because it has the potency to specifically eradicate systemic tumors and control metastases without damaging normal cells. A favorable approach to antigen-specific immunotherapy is the use of DNA vaccines based on their safety, stability, and ease of preparation (see refs. 3, 4 for review). However, DNA vaccines are poorly immunogenic. Thus, the potency of DNA vaccines needs to be enhanced by using methods to target DNA to the professional antigen-presenting cells and by modifying the properties of antigen-expressing antigen-presenting cells to boost vaccine-elicited immune responses. Several approaches have been developed to enhance DNA vaccine potency (see refs. 5, 6 for review).One particular approach to enhance DNA vaccine potency involves the use of intracellular targeting strategies to enhance MHC class I and class II antigen presentation in dendritic cells. Our previous studies have explored the linkage of calreticulin (CRT), a Ca 2+ -binding protein located in the endoplasmic reticulum (see ref. 7 for review) to a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, for the develo...

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