Distinct response to GDF15 knockdown in pediatric and adult glioblastoma cell lines

Abstract

Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumor affecting adults. In pediatric patients, GBM exhibits genetic variations distinct from those identified in the adult GBM phenotype. This tumor exhibits complex genetic changes leading to malignant progression and resistance to standard therapies including radiotherapy and temozolomide treatment. The GDF15 gene codes for a growth factor whose expression is altered in the presence of inflammations and malignancies. GDF15 is associated with a poor prognosis and with radio- and chemoresistance in a variety of tumors. The aim of this study was to compare the response to GDF15 knockdown in adult (U343) and pediatric (KNS42) GBM cell line models.

Methods: The expression of the GDF15 gene was investigated by qRT-PCR and overexpression was identified in both GBM cell lines. The KNS42 and U343 cell lines were submitted to lentiviral transduction with shRNA of GDF15 and validated at the protein level. To understand the difference between cell lines, RNAseq was performed after GDF15 knockdown.

Results: The data obtained demonstrated that the pathways were differentially expressed in adult GBM and pediatric GBM cell lines. This was confirmed by functional assays perfomed after independent treatments (radiotherapy and TMZ).

Conclusion: These results demonstrated that GBM cell lines had distinct responses to GDF15 knockdown, a fact that can be explained by the different molecular profile of pediatric and adult GBM.

Keywords: GDF15; Glioblastoma; RNAseq; Radiotherapy; ShRNA; Temozolomide.