Recently, much research effort has been intensely focused on the roles of dysregulated miRNA expression in various human cancer types including human EOC (14
). Many studies have shown that abberant miRNAs are asscociated with proliferation, apoptosis, metastasis, and chemoresistance of tumor cells (16
). Thus, identification of the important miRNA expression signatures in EOC development and progression will be helpful to find potential diagnostic and prognostic markers for EOC diagnosis and treatment.
Up to date, there have been many published research studies about the correlation of miRNAs with EOC. Lu et al
reported that hypermethylation of let-7a-3 in epithelial ovarian cancer was associated with low insulin-like growth factor-II expression and favorable prognosis (19
). Additionally, the beneficial impact of the addition of paclitaxel on EOC survival has been significantly linked to let-7a levels, and it has been shown that miRNAs such as let-7a may be useful markers for the selection of chemotherapeutic agents in EOC management (20
). Lou et al
reported that microRNA-21 could promote the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein (21
). In other studies, several other microRNAs have been reported to be associated with chemotherapy resistance, such as miR-214, miR-130a, miR-27a and miR-451 (22
). Although miR-100 was reported to be downregulated in human EOC by other research groups, the clinicopathological or prognostic significance of miR-100 in EOC is still unknown. In nasopharyngeal cancer, underexpressed miR-100 was found to lead to PLK1 overexpression, which in turn contributes to NPC progression (25
). However, in prostate cancer, it was reported that a high level of miR-100 was related to biochemical recurrence of localized prostate cancer in patients treated with radical prostatectomy (26
). Recently, Zheng and his group reported that miR-100 could regulate cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia (27
). From the above studies, it may be concluded that miRNA oncogenes and tumor suppressors show different patterns in different tumor types.
In the present study, we firstly showed that the mean level of miR-100 expression in EOC tissues was significantly higher than that in the matched normal tissues. Also, the expression level of miR-100 was significantly lower in EOC patients with advanced clinical stage (III/IV) compared with those with clinical stage I/II. Meanwhile, we showed that low miR-100 expression was closely correlated with advanced FIGO stage, high serum CA125 level and lymph node involvement. Furthermore, patients with low miR-100 expression showed poorer survival than those with high miR-100 expression. A multivariate analysis with the Cox proportional hazards showed that the status of miR-100 expression was an independent predictor of overall survival in EOC. Then, we analyzed the effect of miR-100 expression on the growth of EOC cells and its possible mechanisms. Overexpression of miR-100 could induce growth suppression in human EOC cells, while downregulation of miR-100 could promote growth of EOC cells. PLK1 is a serine/threonine kinase that functions to regulate many stages of mitosis (28
). The overexpression of PLK1 has been found in many human cancers, including ovarian carcinoma (29
). It has been reported that the overexpression of PLK1 could affect growth, apoptosis, metastasis and chemo-or radioresistance in human cancers (30
). Weichert et al
showed that PLK1 is a novel independent prognostic marker in ovarian carcinomas (29
). Additionally, silencing of Chk1 and PLK1 could enhance radiation-or cisplatin-induced cytotoxicity in human ovarian cancer cells (32
). In our study, we show that overexpression of miR-100 could inhibit the expression of PLK1 protein in EOC cells. So, it can be demonstrated that miR-100 negatively regulated PLK1 at the post-translational level, acting as a tumor suppressor in the EOC. In vitro
luciferase assay further suggested that PLK1 is the target gene of miR-100. Importantly, siRNA-mediated downgulation of PLK1 could recapitulate the tumor suppressor function of miR-100, and overexpression of PLK1 could partly rescue the reduced cellular proliferation observed upon miR-100 upregulation in SKOV-3 cells, demonstrating that PLK1 is an important functional target of miR-100 in this model.
In conclusion, this study suggests that miR-100 is downregulated in human EOC and low miR-100 expression may be a poor prognostic factor. Also, miR-100 can significantly inhibit growth of EOC cells by targeting PLK1. Thus, this miR-100/PLK1 signaling pathway may provide therapeutic targets for human EOCs. This study has several limitations. Firstly, the number of tissue samples is small, and further investigation of a larger case population is needed to confirm the prognostic significance of miR-100 expression in EOC. Future investigations using patient samples are needed to further support the function of miR-100 in EOC.