Department of Orthopedics Trauma, Changhai Hospital, Second Military Medical University, Shanghai, China.
Department of Oncology, NO.113 Hospital of People's Liberation Army, Ningbo, China.
Biosci Rep. 2018 Mar 21;38(2). doi: 10.1042/BSR20170339. Print 2018 Apr 27.
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 and 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 and Therefore, miR-422a could be developed as a novel therapeutic target in osteosarcoma.
骨肉瘤是儿童和青少年中最常见的原发性恶性骨肿瘤。然而，骨肉瘤发生和进展的潜在机制尚不清楚。在本研究中，我们评估了骨肉瘤组织和相邻正常组织中 miRNAs 的表达谱。我们发现 miR-422a 在骨肉瘤组织和细胞系中表达下调。此外，我们观察到在骨肉瘤细胞和临床样本中，miR-422a 的启动子区域上抑制性 H3K9me3 和 H3K27me3 水平显著升高，而活性 H3K4me3 水平降低。上调 miR-422a 通过抑制骨肉瘤细胞生长并诱导细胞凋亡和细胞周期停滞，表现出 和 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 的恢复和 BCL2L2 和 KRAS 的敲低促进了骨肉瘤细胞的凋亡并诱导了细胞周期停滞。综上所述，本研究表明，miR-422a 可能通过抑制 BCL2L2 和 KRAS 的翻译，在骨肉瘤中作为一种肿瘤抑制因子发挥作用。因此，miR-422a 可以作为骨肉瘤的一种新的治疗靶点。
