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.
Highlights
Oral cancer, a major subtype of head and neck cancers, is one of the 10 most commonly diagnosed cancers, and more than 90% of oral malignancies are squamous cell carcinomas (OSCC) [1, 2]
These findings indicate that RUNX3 expression in oral squamous cell carcinoma (OSCC) cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors
Hematoxylin and eosin (H&E) staining indicated that bone was intermingled with tumor due to aggressive tumor growth and serious bone loss in shCTRL cell-injected mice, whereas a broad tumor front and clear interface between the bone and tumor were observed in shRUNX3 cell-injected mice (Figure 1E)
Summary
A major subtype of head and neck cancers, is one of the 10 most commonly diagnosed cancers, and more than 90% of oral malignancies are squamous cell carcinomas (OSCC) [1, 2]. Despite the improved treatment of OSCC, the 5-year survival rate for oral cancer, approximately 63 percent, is less than the 5-year survival rate for all cancers [3]. Oral cancer readily invades the neighboring jawbone, which increases mortality [4]. When oral cancer directly invades the bone of the maxilla and/or the mandible, patients experience severe dysfunctions in speech, mastication, and/or swallowing and should be treated with a surgical resection of the jawbone, which causes severe physical and psychological problems [5]. Bone invasion is a risk factor for mandibular osteoradionecrosis and must be considered when planning radiotherapy [6]. Since bone invasion is closely associated with poor prognosis in oral cancer, finding efficient predictive marker or www.impactjournals.com/oncotarget therapeutic target molecules is required for controlling OSCC bone invasion
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