Cervical cancer remains one of the leading causes of cancer death in women worldwide . In spite of the development of advanced therapeutic strategies, the prognosis in patients with this cancer varies significantly and is hard to predict. Treatment outcome still depends primarily on early detection and diagnosis. Recent studies have demonstrated that some abnormal molecular biology changes may play central roles in the tumorigenesis and the development of cervical cancer [18–24]. For example, Liu et al.  reported that genomic amplification of hTERC gene may be associated with more progressive cervical cancer; Imura et al.  demonstrated that Lam-5 was a useful biomarker in the evaluation of invasiveness in cervical adenocarcinoma. Therefore, it is critical to identify biomarkers for the early diagnosis and the early identification of patients with a high risk of treatment failures, in order to modify therapeutic methods for improving overall survival of patients with cervical cancer.
miR-224 is a family of miRNA precursors found in mammals, including humans. It was identified and ends mapped by cloning from Weri cells in human. The sequence of miR-224 maps to chromosome X . Accumulating evidences for differential expression of miR-224 in various types of human cancer suggest that it may be play a crucial role in tumor biology. However, it is also characterized by contradictory properties, since it can promote or inhibit cancer cell growth, depending on the malignancy type. For example, miR-224 is one of the most commonly up-regulated miRNAs in hepatocellular carcinoma . Overexpression of miR-224 in liver cells was reported to increase cell proliferation and apoptosis as well as cell migration and invasion . Up-regulated miR-224 was also identified in a subtype of medulloblastomas. Exogenous expression of miR-224 was found to inhibit proliferation, increase radiation sensitivity and reduce anchorage-independent growth of medulloblastoma cells . In breast cancer cell lines, Huang et al.  found that the overexpression of miR-224 which plays an important role in metastasis of cancer cells to the bone by directly suppressing the RKIP tumor suppressor. In addition to these, the upregulation of miR-224 was also shown in aggressive pancreatic ductal adenocarcinoma , clear cell renal cell carcinoma , thyroid cancer  and bladder cancer . In contrast, a downregulation of miR-224 has been observed in ovarian cancer , prostate cancer  and oral carcinoma .
Observations mentioned above of upregulation or downregulation of miR-224 in different tumor types suggest that miR-224 may have different functions in cancer development depending on the cell type involved. Previous study has shown miR-224 to have increased expression in cervical cancer . For a more comprehensive insight into the clinical value of miR-224, we in the present study performed a real-time quantitative RT-PCR assay to explore the expression profile of this miRNA as well as to investigate its association with clinicopathological features of cervical cancer patients. Our data proved that miR-224 expression was significantly higher in cervical cancer compared with that in adjacent normal tissues. In addition, miR-224 expression was also proved to be associated with histological grade, FIGO stage, HPV status, lymph node metastasis, and vascular invasion for high miR-224 expression was more frequently detected in cervical cancer with poor differentiation, advanced FIGO stage, positive HPV infection, lymph node metastasis, and vascular invasion, which strongly suggested that miR-224 was involved in the invasion and metastasis of cervical cancer. More importantly, we proved that miR-224 expression was significantly associated with overall survival of patients with cervical cancer. In support of this, Kaplan-Meier analysis of overall survival showed that patients with tumors of high miR-224 expression tend to have a significantly shorter overall survival compared with patients whose tumors do not, indicating that high miR-224 expression is a marker of poor prognosis for patients with cervical cancer. Cox proportional hazards model adjusted for known prognostic variables such as histological grade, FIGO stage, HPV status, lymph node metastasis, and vascular invasion proved that miR-224 was an independent prognostic marker for cervical cancer. Thus, miR-224 could be used as a molecular prognostic marker additive to the known prognostic indicator, in order to identify patients who are more likely to have higher risk of death, thus, should receive more aggressive treatment.
In conclusion, our data indicated that miR-224 upregulation was associated with aggressive progression and poor prognosis in cervical cancer. MiR-224 was identified for the first time as an independent marker for predicting the clinical outcome of cervical cancer patients.