Decreased WWOX expression promotes angiogenesis in osteosarcoma
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Jia Wen1,*, Zongchao Xu2,*, Jiazhen Li3, Yingqiang Zhang1, Wenzhe Fan1, Yu Wang1, Mingjian Lu1 and Jiaping Li1
1Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, The People’s Republic of China
2Emergency Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, The People’s Republic of China
3Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, The People’s Republic of China
*These authors should be considered co-first authors
Jiaping Li, email: firstname.lastname@example.org
Keywords: osteosarcoma, WWOX, angiogenesis, RUNX2, bcl-2
Received: December 01, 2016 Accepted: March 30, 2017 Published: April 15, 2017
WWOX (WW domain-containing oxidoreductase) is known to be an important tumor suppressor in cancer. In this study, we used samples from 201 osteosarcoma patients to investigate the effects of WWOX on angiogenesis and invasion. WWOX levels were negatively correlated with RUNX2 and VEGF levels, but were not correlated with OPN levels. Among the clinicopathological characteristics examined, WWOX was associated only with response to neoadjuvant chemotherapy, and its expression in osteosarcoma tissues was a predictor of disease-free survival. WWOX promoted apoptosis and inhibited invasion and expression of bcl-2, OPN, RUNX2, and VEGF in osteosarcoma cells in vitro. In MG-63 cells, bcl-2 increased VEGF expression, while RUNX2 increased VEGF and OPN expression. Administration of DNA methylation inhibitors increased WWOX expression in MG-63 cells and methylation of WWOX gene promoter CpG island in the osteosarcoma of patients was associated with suppression of WWOX expression. Overexpression of WWOX in osteosarcoma cells inhibited tube formation in co-cultured HUVEC cells, and high WWOX expression was associated with decreased microvessel density (MVD). These results suggest that reduced WWOX expression in osteosarcoma inhibits apoptosis, promotes invasion and increases MVD.
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