Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.
The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease.
Kurek
Kyle C
KC
Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Del Mare
Sara
S
Salah
Zaidoun
Z
Abdeen
Suhaib
S
Sadiq
Hussain
H
Lee
Suk-Hee
SH
Gaudio
Eugenio
E
Zanesi
Nicola
N
Jones
Kevin B
KB
DeYoung
Barry
B
Amir
Gail
G
Gebhardt
Mark
M
Warman
Matthew
M
Stein
Gary S
GS
Stein
Janet L
JL
Lian
Jane B
JB
Aqeilan
Rami I
RI
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human