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    • br Materials and methods br

    2019-06-10


    Materials and methods
    Results
    Discussion Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common type of primary bone malignancy [20]. Over the past few decades, the introduction of combinatorial chemotherapy has improved the 5-year overall survival rate of patients with osteosarcoma to approximately 50–60% [21]. However, osteosarcoma-related morbidity remains high due to the difficulty of early diagnosis and the lack of efficient therapeutic approaches for osteosarcoma. Therefore, it is necessary to identify highly sensitive and specific diagnostic and prognostic biomarkers to diagnose osteosarcoma at an early stage and initiate aggressive therapy. Studies have shown that miR-223 has a crucial role in cancer development. Additionally, miR-223 abnormal expression was found in several cancer types [22,23]. More importantly, serum miRNA expression has been shown to be a promising candidate for early detection and prognosis in cancer patients [24]. A recent study showed that miR-223 is involved in osteosarcoma opiod receptors progression and proliferation [18]. However, the role of miR-223 as a serum diagnostic and prognostic biomarker has not been previously explored in osteosarcoma patients. In the present study, we quantified the serum expression levels of miR-223 in osteosarcoma patients and healthy controls and then assessed the potential value of miR-223 as a serum diagnostic and prognostic marker in osteosarcoma patients. The results from our study show for the first time that the expression of miR-223 was remarkably decreased in the serum of osteosarcoma patients and in osteosarcoma cancer cell lines. Furthermore, we showed that the expression of miR-233 could be used to discriminate osteosarcoma from healthy controls (AUC=0.962), with a specificity of 86.4% and a sensitivity 97.2%. Notably, decreased serum miR-223 levels were found to be significantly associated with distant cancer metastasis and advanced clinical stage in osteosarcoma patients, which suggests that miR-223 might act as a tumor suppressor in the development of osteosarcoma. This finding is consistent with previous findings that miR-223 could inhibit osteosarcoma cell cycle progression and proliferation [18]. miRNAs can act as oncogenes or tumor suppressor in multiple types of cancers when abnormally expressed [25]. Similar to other miRNAs, the expression and role of miR-223 significantly varies in different types of cancer. Previous studies have shown that miR-223 is significantly downregulated in cancer tissues of patients with prostate cancer, suggesting that miR-223 may act as a tumor suppressor in prostate cancer [26]. Conversely, miR-223 has also been reported to be overexpressed in other types of cancers, such as esophageal carcinoma and gastric cancer [27,28]. Predicting the clinical outcomes of osteosarcoma patients is important for better treatment and therapeutic strategies. Previous studies have found that the abnormal expression of miR-223 was associated with the development and prognosis of lymphoma [29]. In the present study, we assessed the prognostic role of miR-223 in patients with osteosarcoma and showed that serum miR-221 is a potential independent and effective prognostic biomarker for osteosarcoma, particularly for patients with advanced clinical stage and distant metastasis. In addition, the transwell invasion assay showed that miR-223 mimics significantly inhibited the invasion of MG-63 cells, which suggests that miR-223 may play a role in osteosarcoma metastasis. Previous studies have shown that miR-223/epithelial cell transforming sequence 2 (Ect2) signaling might be an important pathway regulating cell cycle progression and proliferation in osteosarcoma. Moreover, miR-223/Ect2 signaling was shown to be correlated with the recurrence and the poor response to chemotherapy in osteosarcoma [30]. In addition, inhibition of miR-223 expression promotes osteosarcoma cell proliferation by targeting Ect2 activation [31]. Furthermore, Ect2 expression is elevated in various tumor cell lines and tissues, including lung cancer, esophageal cancer, pancreatic cancer and oral cancer, which suggests that Ect2 may function as a proto-oncogene [32,33]. Therefore, we speculated that miR-223 may inhibit cell invasion by negatively regulating Ect2 expression during the progression of osteosarcoma. Future studies are necessary to determine the downstream functional targets of miR-223 in osteosarcoma. The results of the present study and other similar studies suggest that miR-223 is a potential biomarker in cancer development. However, it should be noted that all of these studies were collected in one center with relatively small number of samples. Therefore, future studies with a larger sample size are necessary to confirm these results.