Yuan Hongmou, Gao Yanjun
Department of Orthopaedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China.
Oncol Rep. 2015 Nov;34(5):2706-14. doi: 10.3892/or.2015.4242. Epub 2015 Sep 1.
Osteosarcoma is a high-grade malignant bone neoplasm. Although the introduction of chemotherapy has reduced its mortality, >50% of patients develop chemoresistance and have an extremely poor prognosis due to pulmonary metastasis. Several molecular pathways contributing to osteosarcoma development and progression have recently been identified. Various studies have addressed the genes involved in the metastasis of osteosarcoma. However, the highly complex molecular mechanisms of metastasis remain to be elucidated. Recent studies have emphasized causative links between aberrant microRNA expression patterns and osteosarcoma progression. miR-1908 is dysregulated in certain human types of cancer. The expression pattern, clinical significance and biological role of miR-1908 in osteosarcoma, however, remain largely undefined. In the present study, we showed that miR-1908 was markedly upregulated in osteosarcoma cells and tissues compared with normal bone tissues using RT-qPCR. miR-1908 upregulation in osteosarcoma tissues was significantly associated with cell proliferation, invasion, advanced TNM stage and tumor growth. Both gain- and loss-of-function studies showed that miR-1908 markedly increased the ability of osteosarcoma cells to proliferate and to invade through Matrigel in vitro. Analyses using mouse xenograft model revealed that xenografts of miR-1908 stable-expressing osteosarcoma cells exhibited a significant increase in tumor volume and weight, compared with the control group. Subsequent investigations revealed that miR-1908 directly inhibited the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of PTEN, we identified PTEN as a direct target of miR-1908. Collectively, the results showed that, miR-1908 promotes proliferation and invasion of osteosarcoma cells by repressing PTEN expression.
骨肉瘤是一种高级别恶性骨肿瘤。尽管化疗的引入降低了其死亡率，但超过50%的患者会产生化疗耐药性，且由于肺转移，预后极差。最近已经确定了几种促成骨肉瘤发生和进展的分子途径。各种研究都探讨了与骨肉瘤转移相关的基因。然而，转移的高度复杂分子机制仍有待阐明。最近的研究强调了异常微小RNA表达模式与骨肉瘤进展之间的因果联系。miR-1908在某些人类癌症类型中表达失调。然而，miR-1908在骨肉瘤中的表达模式、临床意义和生物学作用在很大程度上仍不明确。在本研究中，我们使用RT-qPCR表明，与正常骨组织相比，miR-1908在骨肉瘤细胞和组织中明显上调。骨肉瘤组织中miR-1908的上调与细胞增殖、侵袭、晚期TNM分期和肿瘤生长显著相关。功能获得和功能缺失研究均表明，miR-1908显著增强了骨肉瘤细胞在体外增殖和通过基质胶侵袭的能力。使用小鼠异种移植模型进行的分析显示，与对照组相比，miR-1908稳定表达的骨肉瘤细胞异种移植瘤的体积和重量显著增加。随后的研究表明，miR-1908直接抑制10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）的表达。使用携带PTEN 3'-非翻译区（3'-UTR）的荧光素酶报告基因，我们确定PTEN是miR-1908的直接靶标。总体而言，结果表明，miR-1908通过抑制PTEN表达促进骨肉瘤细胞的增殖和侵袭。
