Loss of RUNX3 expression inhibits bone invasion of oral squamous cell carcinoma
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Junhee Park1,2, Hyun-Jeong Kim2, Ki Rim Kim3, Sun Kyoung Lee2, Hyungkeun Kim2,4, Kwang-Kyun Park1,2,4, Won-Yoon Chung1,2,4
1Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea
2Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea
3Department of Dental Hygiene, Kyungpook National University, Sangju 742-711, Korea
4Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea
Won-Yoon Chung, email: [email protected]
Kwang-Kyun Park, email: [email protected]
Keywords: oral squamous cell carcinoma, bone invasion, runt-related transcription factor 3, transforming growth factor-β
Received: October 08, 2015 Accepted: December 15, 2016 Published: December 21, 2016
High recurrence and lower survival rates in patients with oral squamous cell carcinoma (OSCC) are associated with its bone invasion. We identified the oncogenic role of RUNX3 during bone invasion by OSCC. Tumor growth and the generation of osteolytic lesions were significantly inhibited in mice that were subcutaneously inoculated with RUNX3-knockdown human OSCC cells. RUNX3 knockdown enhanced TGF-β-induced growth arrest and inhibited OSCC cell migration and invasion in the absence or presence of transforming growth factor-β (TGF-β), a major growth factor abundant in the bone microenvironment. RUNX3 knockdown induced cell cycle arrest at the G1 and G2 phases and promoted G2 arrest by TGF-β in Ca9.22 OSCC cells. RUNX3 knockdown also inhibited both the basal and TGF-β-induced epithelial-to-mesenchymal transition by increasing E-cadherin expression and suppressing the nuclear translocation of β-catenin. In addition, the expression and TGF-β-mediated induction of parathyroid hormone-related protein (PTHrP), one of key osteolytic factors, was blocked in RUNX3-knockdown OSCC cells. Furthermore, treating human osteoblastic cells with conditioned medium derived from RUNX3-knockdown OSCC cells reduced the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin ratio compared with treatment with conditioned medium from RUNX3-expressing cells. These findings indicate that RUNX3 expression in OSCC cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors. RUNX3 alone or in combination with TGF-β and PTHrP may be a useful predictive biomarker and therapeutic target for bone invasion by oral cancer.
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