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微小 RNA-873 通过靶向 HOXA9 抑制 Wnt/β-连环蛋白通路来抑制骨肉瘤的侵袭表型。

MicroRNA‑873 targets HOXA9 to inhibit the aggressive phenotype of osteosarcoma by deactivating the Wnt/β‑catenin pathway.

机构信息

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.

出版信息

Int J Oncol. 2019 May;54(5):1809-1820. doi: 10.3892/ijo.2019.4735. Epub 2019 Feb 28.


DOI:10.3892/ijo.2019.4735
PMID:30816476
Abstract

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.

摘要

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。

相似文献

[1]
MicroRNA‑873 targets HOXA9 to inhibit the aggressive phenotype of osteosarcoma by deactivating the Wnt/β‑catenin pathway.

Int J Oncol. 2019-2-28

[2]
Nasopharyngeal carcinoma‑associated gene 6 inhibits cell viability, migration, invasion and induces apoptosis in osteosarcoma cells by inactivating the Wnt/β‑catenin signaling pathway.

Mol Med Rep. 2021-2

[3]
Long noncoding RNA KCNQ1OT1 contributes to tumor growth and activates Wnt/β‑catenin signaling in osteosarcoma by targeting the miR‑3666/KLF7 axis.

Int J Mol Med. 2021-1

[4]
Overexpression of miR‑214 promotes the progression of human osteosarcoma by regulating the Wnt/β‑catenin signaling pathway.

Mol Med Rep. 2017-4

[5]
lncRNA‑CASC15 promotes osteosarcoma proliferation and metastasis by regulating epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway.

Oncol Rep. 2021-5

[6]
Overexpressing circular RNA hsa_circ_0002052 impairs osteosarcoma progression via inhibiting Wnt/β-catenin pathway by regulating miR-1205/APC2 axis.

Biochem Biophys Res Commun. 2018-6-5

[7]
MicroRNA‑873 inhibits the progression of thyroid cancer by directly targeting ZEB1.

Mol Med Rep. 2019-6-12

[8]
MicroRNA-221 Promotes Cell Proliferation and Inhibits Apoptosis in Osteosarcoma Cells by Directly Targeting FBXW11 and Regulating Wnt Signaling.

Arch Med Res. 2021-2

[9]
MicroRNA-939-5p directly targets IGF-1R to inhibit the aggressive phenotypes of osteosarcoma through deactivating the PI3K/Akt pathway.

Int J Mol Med. 2019-9-5

[10]
MicroRNA-1294 targets HOXA9 and has a tumor suppressive role in osteosarcoma.

Eur Rev Med Pharmacol Sci. 2018-12

引用本文的文献

[1]
Modulation of immunosuppressive cells and noncoding RNAs as immunotherapy in osteosarcoma.

Front Immunol. 2022

[2]
Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential.

Cancer Cell Int. 2022-11-14

[3]
circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis.

Int J Oncol. 2022-4

[4]
Osteosarcoma and Metastasis.

Front Oncol. 2021-12-10

[5]
MiR-873-5p: A Potential Molecular Marker for Cancer Diagnosis and Prognosis.

Front Oncol. 2021-10-5

[6]
Osteosarcoma Pathogenesis Leads the Way to New Target Treatments.

Int J Mol Sci. 2021-1-15

[7]
Oncogenic and tumor suppressor function of MEIS and associated factors.

Turk J Biol. 2020-12-14

[8]
Role of microRNAs in the crosstalk between osteosarcoma cells and the tumour microenvironment.

J Bone Oncol. 2020-9-28

[9]
miR-429 inhibits osteosarcoma progression by targeting HOXA9 through suppressing Wnt/β-catenin signaling pathway.

Oncol Lett. 2020-9

[10]
Circular RNA SMARCA5 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by miR-19b-3p/HOXA9 axis.

Onco Targets Ther. 2019-8-30

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