p63 regulates cell proliferation and cell cycle progression‑associated genes in stromal cells of giant cell tumor of the bone

Lau,Carol  Po Ying; Ng,Patrick  Kwok Shing; Li,Man  Shan; Tsui,Stephen  Kwok Wing; Huang,Lin; Kumta,Shekhar  Madhukar

doi:10.3892/ijo.2012.1727

p63 regulates cell proliferation and cell cycle progression‑associated genes in stromal cells of giant cell tumor of the bone

Authors:
- Carol Po Ying Lau
- Patrick Kwok Shing Ng
- Man Shan Li
- Stephen Kwok Wing Tsui
- Lin Huang
- Shekhar Madhukar Kumta
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Affiliations: Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, P.R. China, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, P.R. China, Division of Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR, P.R. China
Published online on: December 3, 2012 https://doi.org/10.3892/ijo.2012.1727
Pages: 437-443
Copyright: © Lau et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Giant cell tumor of bone (GCT) is a destructive neoplasm of uncertain etiology that affects the epiphyseal ends of long bones in young adults. GCT stromal cells (GCTSCs) are the primary neoplastic cells of this tumor and are the only proliferating cell component in long-term culture, which recruits osteoclast-like giant cells that eventually mediate bone destruction. The oncogenesis of GCT and factors driving the neoplastic stromal cells to proliferate extensively and pause at an early differentiation stage of pre-osteoblast lineage remain unknown. Overexpression of p63 was observed in GCTSCs and there is growing evidence that p63 is involved in oncogenesis through different mechanisms. This study aimed to understand the specific role of p63 in cell proliferation and oncogenesis of GCTSCs. We confirmed p63 expression in the mononuclear cells in GCT by immunohistochemical staining. By real-time PCR analysis, we showed a higher level (>15‑fold) of TAp63 expression in GCTSCs compared to that in mesenchymal stem cells. Furthermore, we observed that knockdown of the p63 gene by siRNA transfection greatly reduced cell proliferation and induced cell cycle arrest at S phase in GCTSCs. We found that the mRNA expression of CDC2 and CDC25C was substantially suppressed by p63 knockdown at 24-72 h. Moreover, p63 was found to be recruited on the regulatory regions of CDC2 and CDC25C, which contain p53-responsive elements. In summary, our data suggest that p63 regulates GCTSC proliferation by binding to the CDC2 and CDC25C p53-REs, which may inhibit the p53 tumor suppressor activity and contribute to GCT tumorigenesis.

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