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母系胚胎亮氨酸拉链激酶是骨肉瘤预后不良的标志物和治疗靶点。

Maternal embryonic leucine zipper kinase serves as a poor prognosis marker and therapeutic target in osteosarcoma.

机构信息

Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.

Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.

出版信息

Oncol Rep. 2020 Sep;44(3):1037-1048. doi: 10.3892/or.2020.7686. Epub 2020 Jul 13.

Abstract

Osteosarcoma is the most common primary malignancy of bones and frequently affects young children and adolescents. There are several challenges associated with treating osteosarcoma owing to the aggressiveness of the disease, as well as the risk of chemoresistance. Numerous studies are being performed with the aim of identifying improved prognostic and therapeutic markers for this malignancy. Maternal embryonic leucine zipper kinase (MELK) is an oncogene that has been studied in several types of cancer in recent years. In the present study, the expression of MELK in osteosarcoma and normal tissue samples was examined, and the effects of MELK expression on osteosarcoma cellular proliferation, metastasis, the cell cycle and apoptosis were demonstrated using CCK‑8, wound healing, migration and invasion and apoptosis assays. The role of MELK in cancer progression in osteosarcoma was determined, revealing the association between MELK expression and prognosis of osteosarcoma. It was demonstrated that knockdown of MELK resulted in reduced proliferation, migration and invasion in vitro along with potentiation of apoptosis and cell cycle arrest. Furthermore, the effect of the targeted MELK inhibitor, OTSSP167, on tumor progression of osteosarcoma in vitro and in vivo was assessed. Mechanistically, it was demonstrated that MELK promoted osteosarcoma proliferation and metastasis by regulating PCNA and MMP9 expression via the PI3K/Akt/mTOR signaling pathway. Thus, the present study revealed the oncogenic role played by MELK, and established MELK as a valuable prognostic and therapeutic marker in osteosarcoma.

摘要

骨肉瘤是最常见的原发性骨恶性肿瘤,常发生于儿童和青少年。由于疾病的侵袭性以及化疗耐药的风险,治疗骨肉瘤存在诸多挑战。目前正在进行许多研究,旨在确定这种恶性肿瘤的改善预后和治疗标志物。母系胚胎亮氨酸拉链激酶(MELK)是近年来在多种癌症中研究的一种癌基因。在本研究中,检测了 MELK 在骨肉瘤和正常组织样本中的表达,并通过 CCK-8 法、划痕愈合试验、迁移和侵袭试验以及凋亡试验,证实了 MELK 表达对骨肉瘤细胞增殖、转移、细胞周期和凋亡的影响。确定了 MELK 在骨肉瘤癌症进展中的作用,揭示了 MELK 表达与骨肉瘤预后之间的关联。结果表明,沉默 MELK 可降低体外增殖、迁移和侵袭能力,并增强细胞凋亡和细胞周期阻滞。此外,还评估了靶向 MELK 抑制剂 OTSSP167 对骨肉瘤在体外和体内肿瘤进展的影响。从机制上讲,研究表明 MELK 通过调节 PI3K/Akt/mTOR 信号通路调控 PCNA 和 MMP9 的表达,促进骨肉瘤的增殖和转移。因此,本研究揭示了 MELK 发挥的致癌作用,并确立 MELK 作为骨肉瘤有价值的预后和治疗标志物。

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