Department of Spine Surgery, The Affiliated Foshan Chancheng District Center Hospital of Guangdong Medical University, Foshan, Guangdong 528031, P.R. China.
Mol Med Rep. 2019 Nov;20(5):4262-4270. doi: 10.3892/mmr.2019.10664. Epub 2019 Sep 10.
Growth and differentiation factor 15 (GDF15), a novel divergent member of the transforming growth factor‑β (TGF‑β) superfamily, was previously reported to be overexpressed in various types of cancers and was shown to be involved in tumor metastasis; however, the role of GDF15 in the development and malignant progression of osteosarcoma remains unclear. In the present study, reverse transcription‑quantitative polymerase chain reaction, western blot and ELISA analyses were performed to detect mRNA and protein expression, including that of GDF15, SMAD2 and SMAD3. Wound‑healing and cell invasion assays were conducted to determine the migratory and invasive abilities of osteosarcoma cells. A luciferase assay was performed to evaluate the transcriptional activity of a TGF‑β/SMAD‑responsive luciferase reporter. The Kaplan‑Meier method was used to generate survival curves, with a log‑rank test use to evaluate differences in survival. The results revealed that GDF15 expression was upregulated in metastatic osteosarcoma tissues compared with non‑metastatic osteosarcoma tissues. Patients with osteosarcoma that possessed high serum GDF15 levels exhibited significantly decreased overall survival (OS) and pulmonary metastasis‑free survival (PMFS) time compared with patients with low GDF15 expression. Furthermore, high serum GDF15 was an independent prognostic parameter for poor OS and short PMFS. Additionally, it was observed that the knockdown of GDF15 attenuated the migration and invasion of osteosarcoma cells. Silencing GDF15 markedly suppressed the TGF‑β signaling pathway. In conclusion, GDF15 may promote osteosarcoma cell metastasis by regulating the TGF‑β signaling pathway, and serum GDF15 levels may be a potential prognostic and pulmonary metastasis‑predictive biomarker in osteosarcoma.
生长分化因子 15（GDF15）是转化生长因子-β（TGF-β）超家族的一种新型分化成员，先前报道其在多种类型的癌症中过表达，并被证明与肿瘤转移有关；然而，GDF15 在骨肉瘤的发展和恶性进展中的作用尚不清楚。在本研究中，通过逆转录-定量聚合酶链反应、western blot 和 ELISA 分析检测了 mRNA 和蛋白质表达，包括 GDF15、SMAD2 和 SMAD3。进行划痕愈合和细胞侵袭实验以确定骨肉瘤细胞的迁移和侵袭能力。进行荧光素酶实验以评估 TGF-β/SMAD 反应性荧光素酶报告基因的转录活性。Kaplan-Meier 法生成生存曲线，对数秩检验用于评估生存差异。结果显示，转移性骨肉瘤组织中的 GDF15 表达上调，与非转移性骨肉瘤组织相比。GDF15 水平较高的骨肉瘤患者的总生存期（OS）和无肺转移生存期（PMFS）显著缩短，与 GDF15 低表达的患者相比。此外，高血清 GDF15 是 OS 不良和 PMFS 短的独立预后参数。此外，还观察到 GDF15 的敲低可减弱骨肉瘤细胞的迁移和侵袭。沉默 GDF15 可显著抑制 TGF-β 信号通路。总之，GDF15 可能通过调节 TGF-β 信号通路促进骨肉瘤细胞转移，血清 GDF15 水平可能是骨肉瘤中潜在的预后和肺转移预测生物标志物。
