GDF15 promotes osteosarcoma cell migration and invasion by regulating the TGF­ß signaling pathway.

ABSTRACT

Growth and differentiation factor 15 (GDF15), a novel divergent member of the transforming growth factor­ß (TGF­ß) 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 transcription­quantitative polymerase chain reaction, western blot and ELISA analyses were performed to detect mRNA and protein expression, including that of GDF15, SMAD2 and SMAD3. Wound­healing 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 TGF­ß/SMAD­responsive luciferase reporter. The Kaplan­Meier method was used to generate survival curves, with a log­rank test use to evaluate differences in survival. The results revealed that GDF15 expression was upregulated in metastatic osteosarcoma tissues compared with non­metastatic osteosarcoma tissues. Patients with osteosarcoma that possessed high serum GDF15 levels exhibited significantly decreased overall survival (OS) and pulmonary metastasis­free 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 TGF­ß signaling pathway. In conclusion, GDF15 may promote osteosarcoma cell metastasis by regulating the TGF­ß signaling pathway, and serum GDF15 levels may be a potential prognostic and pulmonary metastasis­predictive biomarker in osteosarcoma.