Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis

Authors

Caterina Mancarella, IRCCS Istituto Ortopedico Rizzoli
Giulia Caldoni, University of Bologna
Irene Ribolsi, IRCCS Istituto Ortopedico Rizzoli
Alessandro Parra, IRCCS Istituto Ortopedico Rizzoli
Maria Cristina Manara, IRCCS Istituto Ortopedico Rizzoli
Arthur M Mercurio, University of Massachusetts Medical School
Andrea Morrione, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Katia Scotlandi, IRCCS Istituto Ortopedico Rizzoli

Document Type

Article

Publication Date

7-3-2020

Comments

This article is the author’s final published version in Frontiers in Oncology, Volume 10, July 2020, Article number 994.

The published version is available at https://doi.org/10.3389/fonc.2020.00994. Copyright © Mancarella et al.

Abstract

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of EWS progression. The aim of this study was to further define the role of IGF2BP3 in EWS progression. We demonstrated that high IGF2BP3 mRNA expression levels correlated with EWS metastasis and disease progression in well-characterized EWS tumor specimens. EWS tumors with high IGF2BP3 levels were characterized by a specific gene signature enriched in chemokine-mediated signaling pathways. We also discovered that IGF2BP3 regulated the expression of CXCR4 through CD164. Significantly, CD164 and CXCR4 colocalized at the plasma membrane of EWS cells upon CXCL12 stimulation. We further demonstrated that IGF2BP3, CD164, and CXCR4 expression levels correlated in clinical samples and the IGF2BP3/CD164/CXCR4 signaling pathway promoted motility of EWS cells in response to CXCL12 and under hypoxia conditions. The data presented identified CD164 and CXCR4 as novel IGF2BP3 downstream functional effectors indicating that the IGF2BP3/CD164/CXCR4 oncogenic axis may work as critical modulator of EWS aggressiveness. In addition, IGF2BP3, CD164, and CXCR4 expression levels may constitute a novel biomarker panel predictive of EWS progression.

Recommended Citation

Mancarella, Caterina; Caldoni, Giulia; Ribolsi, Irene; Parra, Alessandro; Manara, Maria Cristina; Mercurio, Arthur M; Morrione, Andrea; and Scotlandi, Katia, "Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis" (2020). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 298.
https://jdc.jefferson.edu/pacbfp/298

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

32719743

Language

English