title: p63 regulates cell proliferation and cell cycle progression‑associated             genes in stromal cells of giant cell tumor of the bone.
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.
authors.affiliation: Department of Orthopaedics and Traumatology, The Chinese University                     of Hong Kong, Shatin, N.T., Hong Kong, SAR, P.R. China.
authors.forename: Carol Po Ying
authors.initials: CP
authors.lastname: Lau
authors.forename: Patrick Kwok Shing
authors.initials: PK
authors.lastname: Ng
authors.forename: Man Shan
authors.initials: MS
authors.lastname: Li
authors.forename: Stephen Kwok Wing
authors.initials: SK
authors.lastname: Tsui
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.forename: Shekhar Madhukar
authors.initials: SM
authors.lastname: Kumta
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis; D063646:Carcinogenesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D018816:Genes, cdc; D005870:Giant Cell Tumors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000096:biosynthesis
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D042846:CDC2-CDC28 Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases