Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
Int J Oncol. 2019 May;54(5):1809-1820. doi: 10.3892/ijo.2019.4735. Epub 2019 Feb 28.
Several microRNAs (miRNAs or miRs) that regulate a variety of cancer‑related events are dysregulated in osteosarcoma (OS). An exploration of the specific roles of miRNAs in OS is crucial for the identification of suitable therapeutic targets. Previous studies have shown that miR‑873 plays tumor suppressive or oncogenic roles in different types of cancer. However, whether miR‑873 is implicated in OS carcinogenesis and cancer progression remains poorly understood. In the present study, we demonstrated that the miR‑873 levels were decreased in OS tissues and cell lines. The decreased expression of miR‑873 was related to tumor size, clinical stage and distant metastasis in patients with OS. The introduction of miR‑873 significantly inhibited tumor cell proliferation, migration and invasion in vitro, promoted apoptosis in vitro and restricted tumor growth in vivo. Furthermore, homeobox A9 (HOXA9) was validated as a direct target gene of miR‑873 in OS cells. HOXA9 was markedly expressed in OS tissues, and its upregulation inversely correlated with the miR‑873 levels. Moreover, HOXA9 silencing produced similar effects as observed with miR‑873 overexpression in OS cells. Consistently, the exogenous expression of HOXA9 partially reversed the suppression of the aggressive phenotype induced by miR‑873 overexpression in OS cells. Notably, miR‑873 was able to deactivate the Wnt/β‑catenin pathway in OS cells by regulating HOXA9, both in vitro and in vivo. On the whole, the present study demonstrates that miR‑873 suppresses the development of OS by directly targeting HOXA9 and inhibiting the Wnt/β‑catenin pathway, and suggests that miR‑873 may prove to be useful as a diagnostic biomarker of OS, as well as in the development of novel therapies.
几种调节多种癌症相关事件的 microRNAs(miRNAs 或 miRs)在骨肉瘤(OS)中失调。探索 miRNA 在 OS 中的特定作用对于确定合适的治疗靶点至关重要。先前的研究表明,miR-873 在不同类型的癌症中发挥肿瘤抑制或致癌作用。然而,miR-873 是否参与 OS 癌变和癌症进展仍知之甚少。在本研究中,我们证明 miR-873 的水平在 OS 组织和细胞系中降低。miR-873 表达降低与 OS 患者的肿瘤大小、临床分期和远处转移有关。miR-873 的引入显著抑制了 OS 细胞在体外的增殖、迁移和侵袭,促进了细胞凋亡并限制了体内肿瘤的生长。此外,同源盒 A9(HOXA9)被验证为 OS 细胞中 miR-873 的直接靶基因。HOXA9 在 OS 组织中明显表达,其上调与 miR-873 水平呈负相关。此外,HOXA9 的沉默在 OS 细胞中产生了与 miR-873 过表达观察到的类似效果。一致地,HOXA9 的外源性表达部分逆转了 miR-873 过表达在 OS 细胞中对侵袭表型的抑制作用。值得注意的是,miR-873 通过调节 HOXA9 在体外和体内均可使 OS 细胞中的 Wnt/β-catenin 通路失活。总的来说,本研究表明 miR-873 通过直接靶向 HOXA9 抑制 Wnt/β-catenin 通路来抑制 OS 的发展,并表明 miR-873 可能作为 OS 的诊断生物标志物以及新疗法的开发证明是有用的。
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