Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Int J Mol Med. 2020 Jun;45(6):1803-1813. doi: 10.3892/ijmm.2020.4558. Epub 2020 Mar 31.
Osteosarcoma (OS) is one of the most common malignant tumors in young adults and has a high distant metastasis rate. The p53 protein, a potent prognostic biomarker for patients with OS, is altered in ~50% of OS cases. p53 was reported to exert its effects through regulating the transcription of microRNAs (miRNAs/miRs) and other genes. In the present study, the expression of miR‑181b, a critical OS oncomiR, was shown to be significantly upregulated whereas p53 expression was downregulated within OS tissues and cells; in tissue samples, miR‑181b and p53 were negatively correlated. p53 inhibited the transcription of miR‑181b via targeting its promoter region, whereas miR‑181b bound the TP53 3'‑untranslated region (UTR) to inhibit p53 expression. miR‑181b silencing considerably increased p53, p21, and epithelial‑Cadherin protein levels but decreased Cyclin D1 protein levels in OS cells. In addition, miR‑181b inhibition reduced OS cell proliferation and invasion. In contrast, p53 knockdown had the opposite effects on these proteins and OS cell proliferation and invasion. Above all, p53 knockdown significantly attenuated the effects of miR‑181b inhibition. Moreover, OS cell xenograft assays further confirmed the roles of the miR‑181b/p53 axis in OS growth. In conclusion, miR‑181b and p53 are negatively regulated by one another and therefore form a negative feedback axis that regulates the proliferation and invasion abilities of OS cells. Targeting miR‑181b to inhibit its abnormal upregulation might be a potent strategy for OS treatment.
骨肉瘤（OS）是年轻人中最常见的恶性肿瘤之一，具有很高的远处转移率。p53 蛋白是 OS 患者的一种强有力的预后生物标志物，约有 50%的 OS 病例发生改变。据报道，p53 通过调节 microRNAs（miRNAs/miRs）和其他基因的转录来发挥作用。在本研究中，miR-181b 的表达，一种关键的骨肉瘤致癌 miRNA，在骨肉瘤组织和细胞中显示出显著上调，而 p53 表达下调；在组织样本中，miR-181b 和 p53 呈负相关。p53 通过靶向其启动子区域抑制 miR-181b 的转录，而 miR-181b 结合 TP53 3'非翻译区（UTR）抑制 p53 表达。miR-181b 沉默显著增加了骨肉瘤细胞中 p53、p21 和上皮钙黏蛋白蛋白的水平，但降低了 Cyclin D1 蛋白的水平。此外，miR-181b 抑制减少了骨肉瘤细胞的增殖和侵袭。相反，p53 敲低对这些蛋白和骨肉瘤细胞的增殖和侵袭有相反的作用。最重要的是，p53 敲低显著减弱了 miR-181b 抑制的作用。此外，骨肉瘤细胞异种移植实验进一步证实了 miR-181b/p53 轴在骨肉瘤生长中的作用。总之，miR-181b 和 p53 相互负调控，因此形成一个负反馈轴，调节骨肉瘤细胞的增殖和侵袭能力。靶向 miR-181b 抑制其异常上调可能是骨肉瘤治疗的一种有效策略。
