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Transforming growth factor-β1-regulated fractalkine and its receptor, CX3CR1, mediate human oral Squamous cell, carcinoma-induced bone invasion

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 TGF-β1에 의해 조절되는 fractalkine과 CX3CR1은 사람 구강 편평상피세포암의 골 침윤을 촉진시킨다 
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Dept. of Dentistry/박사
Oral squamous cell carcinoma (OSCC) is a world-wide health problem and its incidence accounts for 1.9-3.5% of all malignant tumors approximately. Despite advances in multimodal treatments, OSCC has a potent activity of local bone invasion; thereby the 5-year survival of patients with OSCC remains less than 50%. Transforming growth factor (TGF)-β1 is a multifunctional polypeptide that elicits numerous cellular effects pertinent to the metastatic process, including cell differentiation, proliferation, modulation of angiogenesis and synthesis of extracellular matrix proteins. However, the role of TGF-β1 in OSCC-induced bone invasion is less well understood. We examined whether TGF-β1 signaling could regulate bone invasion by OSCC in vivo and in vitro. We first established an in vivo model by subcutaneous injection of human TGF-β1 wild or knockdown OSCC cells onto the surface of calvaria in nude mice, which developed tumors for 40 days. Micro-CT analysis revealed that OSCC-induced bone destruction or resorption was inhibited by TGF-β1 knockdown. Histological examination of calvarial sections indicated that TGF-β1 knockdown significantly decreased tumor growth and invasion, and resulted in an obvious recovery of calcium release and the reduced osteoclast formation at the tumor-bone interface. Immunohistochemical analysis showed the reduced expressions of fractalkine, CX3CR1, BMP-4, M-CSF, MMP-2, MMP-9 and PTHrP in calvarial tissues of TGF-β1 knockdown OSCC-inoculated mice compared with wild OSCC-inoculated mice. As the results of in vitro experiments, TGF-β1 enhanced the migration, invasion and uPA activity of OSCC cells. To examine the molecular mechanisms underlying TGF-β1 activity on bone invasion of OSCC cells, we focused on the role of fractalkine, detected by chemokine array with culture media of TGF-β1 wild or knockdown OSCC cells. Fractalkine increased the migration, invasion and uPA activity of OSCC cells. These data suggest that the OSCC-induced bone invasion may be mediated by TGF-β1-regulated chemokines, particularly fractalkine and its receptor CX3CR1.
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2. 학위논문 > 2. College of Dentistry (치과대학) > 박사
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