Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Int J Immunopathol Pharmacol. 2018 Jan-Dec;32:2058738418786656. doi: 10.1177/2058738418786656.
MicroRNAs (miRNAs) as small non-coding RNAs act as either tumor suppressors or oncogenes in human cancers, of which miR-149-5p (miR-149) is involved in tumor growth and metastasis, but its role and molecular mechanisms underlying osteosarcoma growth are poorly understood. The correlation of miR-149 expression with clinicopathological characteristics and prognosis in patients with sarcoma was analyzed by The Cancer Genome Atlas (TCGA) RNA-sequencing data. Osteosarcoma cell growth affected by miR-149 was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. As a result, we found that the expression level of miR-149 was markedly downregulated in human sarcoma samples and were negatively associated with tumor size, acting as an independent prognostic factor for overall survival of the sarcoma patients. Restoration of miR-149 expression suppressed osteosarcoma cell growth, while its knockdown reversed these effects. Furthermore, we identified TNFRSF12A (TNF receptor superfamily member 12A), also called fibroblast growth factor-inducible 14 (Fn14) as a direct target of miR-149, and TNFRSF12A and its ligand TNFSF12 (TNF superfamily member 12), also called tumor necrosis factor-related weak inducer of apoptosis (TWEAK), were both negatively correlated with miR-149 expression in sarcoma samples. Knockdown of TNFRSF12A suppressed cell growth, but its overexpression weakened the antiproliferative effects of miR-149 via the PI3K/AKT (AKT serine/threonine kinase) signaling pathway. Altogether, our findings show that miR-149 functions as a tumor suppressor in osteosarcoma via inhibition of the TWEAK-Fn14 axis and represents a potential therapeutic target in patients with osteosarcoma.
微小 RNA（miRNAs）作为小的非编码 RNA，在人类癌症中充当肿瘤抑制因子或癌基因，其中 miR-149-5p（miR-149）参与肿瘤生长和转移，但它在骨肉瘤生长中的作用和分子机制尚不清楚。通过癌症基因组图谱（TCGA）RNA 测序数据分析 miR-149 表达与肉瘤患者临床病理特征和预后的相关性。通过 3-(4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）和集落形成测定评估 miR-149 对骨肉瘤细胞生长的影响。结果表明，miR-149 的表达水平在人类肉瘤样本中明显下调，与肿瘤大小呈负相关，是肉瘤患者总生存的独立预后因素。恢复 miR-149 的表达抑制骨肉瘤细胞生长，而其敲低则逆转这些效应。此外，我们确定 TNFRSF12A（肿瘤坏死因子受体超家族成员 12A），也称为成纤维细胞生长因子诱导 14（Fn14），是 miR-149 的直接靶标，而 TNFRSF12A 及其配体 TNFSF12（肿瘤坏死因子超家族成员 12），也称为肿瘤坏死因子相关弱凋亡诱导剂（TWEAK），在肉瘤样本中均与 miR-149 的表达呈负相关。TNFRSF12A 的敲低抑制细胞生长，但通过 PI3K/AKT（AKT 丝氨酸/苏氨酸激酶）信号通路过表达削弱了 miR-149 的抗增殖作用。总之，我们的研究结果表明，miR-149 通过抑制 TWEAK-Fn14 轴在骨肉瘤中发挥肿瘤抑制作用，代表骨肉瘤患者的潜在治疗靶点。
