Abstract
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of SHH in bone destruction associated with oral squamous cell carcinomas is still unclear. In this study we analyzed SHH expression and the role played by SHH signaling in gingival carcinoma-induced jawbone destruction. From an analysis of surgically resected lower gingival squamous cell carcinoma mandible samples, we found that SHH was highly expressed in tumor cells that had invaded the bone matrix. On the other hand, the hedgehog receptor Patched and the signaling molecule Gli-2 were highly expressed in the osteoclasts and the progenitor cells. SHH stimulated osteoclast formation and pit formation in the presence of the receptor activator for nuclear factor-κB ligand (RANKL) in CD11b+ mouse bone marrow cells. SHH upregulated phosphorylation of ERK1/2 and p38 MAPK, NFATc1, tartrate-resistant acid phosphatase (TRAP), and Cathepsin K expression in RAW264.7 cells. Our results suggest that tumor-derived SHH stimulated the osteoclast formation and bone resorption in the tumor jawbone microenvironment.
Highlights
Oral squamous cell carcinoma frequently invades into the maxilla and the mandible, and that is associated with a worse prognosis [1]
We reported on the ability of paracrine hedgehog signaling to increase oral squamous cell carcinoma growth in bone through the indirect actions of osteoclastogenesis on bone marrow stromal cells with osteoclast progenitor cells [19]
We demonstrated that Sonic hedgehog (SHH) stimulated osteoclast formation by upregulating the production of RANKL in bone marrow stromal cells
Summary
Oral squamous cell carcinoma frequently invades into the maxilla and the mandible, and that is associated with a worse prognosis [1]. Medullary invaded oral squamous cell carcinoma has been shown to be an independent predictor of reduced overall and disease-specific survival, and this association appears to result from an increased risk of distant metastatic failure [2]. Bone resection as a treatment leads to the postoperative disruption of speech and swallowing function. It is critical that a new approach be generated for the treatment of advanced oral squamous cell carcinoma
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