miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS
miR-422a inhibits osteosarcoma proliferation by targeting BCL2L2 and KRAS
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miR-422a通过靶向BCL2L2和KRAS抑制骨肉瘤增殖
DOI：
10.1042/bsr20170339
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发表时间：
2018-04-27
影响因子：
4
通讯作者：
Ji, Fang
中科院分区：
文献类型：
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作者：
Zhang, Hao;He, Qian-Yun;Ji, Fang
骨肉瘤是儿童青少年最常见的原发恶性骨肿瘤。然而，骨肉瘤发生和发展的潜在机制仍不清楚。在本研究中，我们评估了miRNAs在骨肉瘤组织和邻近正常组织中的表达谱。我们发现miR-422a在骨肉瘤组织和细胞系中的表达下调。此外，我们观察到骨肉瘤细胞和临床标本中miR-422a启动区的抑制性H3K9me3和H3K27me3水平显著升高，而活性H3K4me3水平显著降低。此外，miR-422a的上调在体外和体内都显示出通过抑制骨肉瘤细胞生长、诱导细胞凋亡和细胞周期停滞而产生的抗肿瘤作用。我们还发现miR-422a靶向BCL2L2和KRAS并负调控它们的蛋白表达。此外，miR-422a的修复和BCL2L2和KRAS的敲除促进了骨肉瘤细胞的凋亡和诱导细胞周期停滞。综上所述，本研究表明miR-422a可能通过在体外和体内抑制BCL2L2和KRAS的翻译而在骨肉瘤中发挥肿瘤抑制作用。因此，miR-422a有望成为骨肉瘤治疗的新靶点。
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. However, the underlying mechanism of osteosarcoma carcinogenesis and progression remains unknown. In the present study, we evaluated the expression profile of miRNAs in osteosarcoma tissues and the adjacent normal tissues. We found that the expression of miR-422a was down-regulated in osteosarcoma tissues and cell lines. In addition, we observed significantly elevated levels of repressive H3K9me3 and H3K27me3 and decreased active H3K4me3 on the promote region of miR-422a in osteosarcoma cells and clinical samples. Furthermore, up-regulation of miR-422a exhibited both in vitro and in vivo anti-tumor effects by inhibiting osteosarcoma cell growth and inducing apoptosis and cell cycle arrest. We also found that miR-422a targeted BCL2L2 and KRAS and negatively regulated their protein expression. Furthermore, restoration of miR-422a and knockdown of BCL2L2 and KRAS promoted apoptosis and induce cell cycle arrest in osteosarcoma cells. Taken together, the present study demonstrates that miR-422a may serve as a tumor suppressor in osteosarcoma via inhibiting BCL2L2 and KRAS translation both in vitro and in vivo. Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.