Abstract
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.
Highlights
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, accounting for 30% of all bone malignancies and 3–4% of pediatric tumors [1]
We focused on the role of miR-422a in osteosarcoma because it was seldom reported
Osteosarcoma is a frequently occurred bone tumor characterized by an aggressive clinical course [12,13]
Summary
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, accounting for 30% of all bone malignancies and 3–4% of pediatric tumors [1]. Osteosarcoma is associated with poor prognosis and high morbidity [2]. Exploration of new targets is critical for developing novel therapeutic strategies for osteosarcoma patients. Accumulating studies have demonstrated that miRNAs play crucial roles in regulating diverse biological processes including cell proliferation, apoptosis, differentiation, and migration [5]. Lei et al have found that miRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting Rho-associated protein kinase 1 (ROCK1) [6]. Another study by Zhang et al has shown that miRNA-143, down-regulated in osteosarcoma, promotes apoptosis and suppresses tumorigenicity by targeting Bcl-2 [7]. Altered expression of individual miRNAs has been associated with prognosis, tumor stage, vascular invasion, and lymph node metastasis in multiple tumor types, including osteosarcoma [8]. It is valuable to explore the miRNAs expression profile and further to identify specific miRNA involved in the osteosarcoma pathogenesis and progression
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