Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression

Kyle C. Kurek, Sara Del Mare, Zaidoun Salah, Suhaib Abdeen, Hussain Sadiq, Suk Hee Lee, Eugenio Gaudio, Nicola Zanesi, Kevin B. Jones, Barry DeYoung, Gail Amir, Mark Gebhardt, Matthew Warman, Gary S. Stein, Janet L. Stein, Jane B. Lian, Rami I. Aqeilan

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)5577-5586
Number of pages10
JournalCancer Research
Volume70
Issue number13
DOIs
StatePublished - 1 Jul 2010

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