Expression of miR-224-5p is associated with the original cisplatin resistance of ovarian papillary serous carcinoma

Abstract

Chemoresistance is a major challenge to successful chemotherapy of ovarian cancer, which represents the leading cause of mortality from gynecologic malignancies. We demonstrated that overexpression of miR-224-5p in ovarian cancer patients is associated with platinum-based chemoresistance using miRNA microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR) validation in vivo, as well as in 4 human ovarian cancer cell lines (C13/OV2008; A2780CP/A2780S) in vitro. In the present study, we aimed to clarify the role of miR-224-5p in regulating the chemoresistance of ovarian cancer. By using the sensitive miRNA transient transfection, we demonstrated expression and bioactivity of miR-224-5p in ovarian cancer cell lines. It is of note that enforced expression of miR-224-5p enhanced chemoresistance to cisplatin in ovarian cancer cells through apoptosis reversion. We predicted and identified the PRKCD gene as one of the targets of miR-224-5p in mediating the primary chemoresistance of ovarian cancer patients. We showed reciprocal expression of miR-224-5p and PRKCD by quantitative analysis in complete response and incomplete response patients in vivo, and 2 pairs of cisplatin resistance and sensitive cell lines in vitro, after either miR-224-5p overexpression or knockdown transfection. Additionally, miR-224-5p and PRKCD can serve as novel predictors and prognostic biomarkers for ovarian papillary serous carcinoma (OPSC) patient response to overall disease-specific survival. Our findings suggest that miR-224-5p may function as an oncogene and induce platinum resistance in OPSC at least in part by downregulating PRKCD, thereby providing a biomarker for predicting chemosensitivity to cisplatin in patients with ovarian cancer.

MicroRNA-224: as a potential target for miR-based therapy of cancer

“…MMP-2 Increase celastrol inhibitory effect on cell migration and invasion Hepatocellular Li et al [56] MMP-9 Increase celastrol inhibitory effect on cell migration and invasion Hepatocellular Li et al [56] API-5 Amplify radiation sensitivity Glioblastoma Upraity et al [57] PDGFR A biomarker for the prognosis of sorafenib-treated patients Hepatocellular Gyöngyösi et al [58] PRKCD Increase resistance to cisplatin Ovarian Zhao et al [59] CD59 Predict the response and outcome of patients treated with R-CHOP Lymphoma Song et al [60] Tumor Biol.…”

“…In ovarian cancer, ectopic expression of miR-224-5p is related to platinum-based chemoresistance. Overexpression of miR-224-5p increases chemoresistance to cisplatin via apoptosis reversion at least in part by downregulating PRKCD in ovarian cancer cells [59]. In diffuse large B cell lymphoma (DLBCL) patients, the expression levels of miR-224 and its target CD59 can predict the response and outcome of patients treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) [60] (Table 1).…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…By targeting p21, it participated in cell cycle regulation at the G1/S checkpoint (236). miR-224 could induce resistance to cisplatin in lung and ovarian cancer cell lines (47, 237). In contrast, miR-224 promoted cisplatin sensitivity in osteosarcoma resistant cells by targeting Rac1 (238).…”

Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function

“…Recent studies have shown that miR-224 is more highly expressed in not only HCC but also esophageal cancer, non-small cell lung cancer, colorectal cancer, cervical cancer and glioma, and this molecule has a proliferative effect on these cancer cells through direct interactions with various tumor-suppressor genes, such as CAMKK2, ADAM17, Homeobox D 10 and RKIP [63][64][65][66][67][68]. Moreover, the clinical relevance of miR-224 had been reported as an indicator of chemoresistance to cisplatin, methotrexate and R-CHOP, radiation sensitivity and a prognostic factor of sorafenib-treated patients [69][70][71][72][73][74]. These findings strongly suggest that miR-224 might have a pivotal role in carcinogenesis and the development of HCC tumors.…”