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von Heyking, K.* ; Roth, L.C.* ; Ertl, M.* ; Schmidt, O.* ; Calzada-Wack, J. ; Neff, F. ; Lawlor, E.R.* ; Burdach, S.* ; Richter, G.H.*

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

Oncotarget 7, 41767-41780 (2016)
Verlagsversion Anhang DOI PMC
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ewing Sarcoma ; Hoxd ; Wnt Signaling ; Endochondral Development ; Metastasis; Peripheral Neuroectodermal Tumors; Osteoblast Differentiation; Molecular Pathogenesis; Homeobox Genes; In-vivo; Expression; Bone; Cancer; Cells; Invasiveness
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Zeitschrift OncoTarget
Quellenangaben Band: 7, Heft: 27, Seiten: 41767-41780 Artikelnummer: , Supplement: ,
Verlag Impact Journals LLC
Verlagsort Albany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)