Research Papers:

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

Kristina von Heyking, Laura Roth, Miriam Ertl, Oxana Schmidt, Julia Calzada- Wack, Frauke Neff, Elizabeth R. Lawlor, Stefan Burdach and Günther H.S. Richter _

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Oncotarget. 2016; 7:41767-41780. https://doi.org/10.18632/oncotarget.9702

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Kristina von Heyking1, Laura Roth1,*, Miriam Ertl1,*, Oxana Schmidt1, Julia Calzada-Wack2, Frauke Neff2, Elizabeth R. Lawlor3, Stefan Burdach1, Günther H.S. Richter1

1Laboratory for Functional Genomics and Transplantation Biology, Children’s Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich Comprehensive Cancer Center (CCCM), and German Translational Cancer Research Consortium (DKTK), Munich, Germany

2Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany

3Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, United States of America

*These authors contributed equally to this work

Correspondence to:

Günther H.S. Richter, email: guenther.richter@tum.de

Keywords: HOXD, metastasis, Ewing sarcoma, WNT signaling, endochondral development

Received: December 02, 2015     Accepted: May 13, 2016     Published: May 30, 2016


Microarray analysis revealed genes of the posterior HOXD locus normally involved in bone formation to be over-expressed in primary Ewing sarcoma (ES). The expression of posterior HOXD genes was not influenced via ES pathognomonic EWS/ETS translocations. However, knock down of the dickkopf WNT signaling pathway inhibitor 2 (DKK2) resulted in a significant suppression of HOXD10, HOXD11 and HOXD13 while over-expression of DKK2 and stimulation with factors of the WNT signaling pathway such as WNT3a, WNT5a or WNT11 increased their expression. RNA interference demonstrated that individual HOXD genes promoted chondrogenic differentiation potential, and enhanced expression of the bone-associated gene RUNX2. Furthermore, HOXD genes increased the level of the osteoblast- and osteoclast-specific genes, osteocalcin (BGLAP) and platelet-derived growth factor beta polypeptide (PDGFB), and may further regulate endochondral bone development via induction of parathyroid hormone-like hormone (PTHLH). Additionally, HOXD11 and HOXD13 promoted contact independent growth of ES, while in vitro invasiveness of ES lines was enhanced by all 3 HOXD genes investigated and seemed mediated via matrix metallopeptidase 1 (MMP1). Consequently, knock down of HOXD11 or HOXD13 significantly suppressed lung metastasis in a xeno-transplant model in immune deficient mice, providing overall evidence that posterior HOXD genes promote clonogenicity and metastatic potential of ES.

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