Pamidronate, farnesyl transferase, and geranylgeranyl transferase‐I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone

Lau, Carol; Huang, Lin; Tsui, Stephen Kwok‐Wing; Ng, Patrick Kwok-Shing; Leung, P. Y.; Kumta, S. M.

doi:10.1002/jor.21249

Cited by 17 publications

(16 citation statements)

References 38 publications

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“…All protocols were approved by the local institutional ethics committee. Primary culture of GCTSCs was established as described previously (16). In brief, freshly obtained GCT tissues were chopped in DMEM containing 10% FBS and 100 U/ml penicillin (PSN).…”

Section: Methodsmentioning

confidence: 99%

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

Lau

et al. 2012

International Journal of Oncology

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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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Section: Methodsmentioning

confidence: 99%

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

Lau

et al. 2012

International Journal of Oncology

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“…RANKL is also an important signaling pathway which plays a vital role in osteoclastogenesis and bone resorption (22,23). Bone resorption is necessary for the establishment and promotion of tumor metastasis in the bone (24,25). In this pathway, RANKL can interact with its receptor RANK, which is on the surface of osteoclast precursors, to enhance activation, formation and survival of osteoclasts in normal stage or tumor stage (26).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of filamin B splice variants in giant cell tumor cells

et al. 2016

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Giant cell tumor of bone (GCT) is the most commonly reported non-malignant bone tumor in Hong Kong. This kind of tumor usually affects people aged 20–40 years. Also, it is well known for recurrence locally, especially when the tumor cannot be removed completely. Filamins are actin-binding proteins which contain three family members, filamin A, B and C. They are the products of three different genes, FLNA, FLNB and FLNC, which can generate various transcript variants in different cell types. In this study, we focused on the effects of FLNBv2 and FLNBv4 toward GCT cells. The only difference between FLNBv2 and FLNBv4 is that FLNBv4 does not contain hinge 1 region. We found that the relative abundance of FLNBv4 varies among different GCT cell lines while the expression level of FLNBv4 in normal osteoblasts was only marginally detectable. In the functional aspect, overexpression of FLNBv4 led to upregulation of RANKL, OCN, OPG and RUNX2, which are closely related to GCT cell survival and differentiation. Moreover, FLNBv4 can have a negative effect on cell viability of GCT cells when compare with FLNBv2. In conclusion, splicing variants of FLNB are differentially expressed in GCT cells and may play a role in the proliferation and differentiation of tumor cells.

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“…Written consent was acquired from the patients, and the study protocol was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee. Primary cultures of GCTB stromal cells were established as previously described . In brief, GCTB tissues from resections were rinsed and minced with scissors in Dulbecco's minimum essential medium (DMEM) containing 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 µg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Simvastatin Possesses Antitumor and Differentiation‐Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone

Lau

Fung

Wong

et al. 2019

Journal Orthopaedic Research

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Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment.

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Pamidronate, farnesyl transferase, and geranylgeranyl transferase‐I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone

Cited by 17 publications

References 38 publications

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

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

Differential expression of filamin B splice variants in giant cell tumor cells

Simvastatin Possesses Antitumor and Differentiation‐Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone

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