title: Loss of RUNX3 expression inhibits bone invasion of oral squamous cell carcinoma.
abstract: 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.
authors.affiliation: Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.|Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Junhee
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Dental Hygiene, Kyungpook National University, Sangju 742-711, Korea.
authors.forename: Ki Rim
authors.initials: KR
authors.lastname: Kim
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: Sun Kyoung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.|Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Hyungkeun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.|Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.|Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
authors.affiliation: Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.|Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.|Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Won-Yoon
authors.initials: WY
authors.lastname: Chung
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D012886:Skull / Q000378:metabolism* / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; C493729:Runx3 protein, human; C505688:TNFSF11 protein, human; D016212:Transforming Growth Factor beta
keywords: bone invasion; oral squamous cell carcinoma; runt-related transcription factor 3; transforming growth factor-β