Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation

Tanaka, Motoyuki; Setoguchi, Takao; Hirotsu, Masataka; Gao, Hui; Sasaki, Hiromi; Matsunoshita, Yukihiro; Komiya, Setsuro

doi:10.1038/sj.bjc.6605060

Cited by 136 publications

(133 citation statements)

References 39 publications

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“…A previous study indicated that FoxM1 regulated the transcription of cell cycle genes including genes encoding the SCF (Skp2-Cks1) ubiquitin ligase complex (42). Another study demonstrated that inhibition of the Notch pathway by γ-secretase inhibitor suppressed the growth of OS in vitro and in vivo due to a decrease in the expression of accelerators of the cell cycle such as Skp2, cyclin D1, and cyclin E1 and E2 (43). Similarly, inhibition of smoothened, a key molecule in the Hedgehog pathway, slowed the growth of OS cells via the suppression of Skp2 and cyclin D1 and E1, but upregulation of p21 (44).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Ding

Han

et al. 2017

Oncology Reports

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Abstract. Osteosarcoma (OS) is a common bone tumor that mainly affects children and young adults. S-phase kinase-associated protein 2 (Skp2) has been characterized to play a critical oncogenic role in a variety of human malignancies. However, the biological function of Skp2 in OS remains largely obscure. In the present study, we elucidated the role of Skp2 in cell growth, cell cycle, apoptosis and migration in OS cells. We found that depletion of Skp2 inhibited cell growth in both MG-63 and SW 1353 cells. Moreover, we observed that depletion of Skp2 triggered cell apoptosis in two OS cell lines. Furthermore, downregulation of Skp2 induced cell cycle arrest in the G0/G1 phase in OS cells. Notably, our wound healing assay results revealed that inhibition of Skp2 suppressed cell migration in OS cells. Invariably, our western blot results demonstrated that depletion of Skp2 in OS cells inhibited activation of pAkt and increased p27 expression in OS cells, suggesting that Skp2 exerted its oncogenic function partly through the regulation of Akt and p27. Our findings revealed that targeting Skp2 could be a promising therapeutic strategy for the treatment of OS.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Ding

Han

et al. 2017

Oncology Reports

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“…The following antibodies were used: PE-conjugated anti-FGFR3 antibody (R&D) and anti-PE Microbeads (Miltenyi Biotec). Cell inoculation was performed as reported earlier (Tanaka et al, 2009). Cells were mixed with a collagen gel, and were inoculated subcutaneously in 5-week-old nude mice.…”

Section: Animal Experimentsmentioning

confidence: 99%

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

et al. 2009

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BACKGROUND: The hypothesis that malignant tumours are generated by rare populations of cancer stem cells that are more tumourigenic than other cancer cells has gained increasing credence. The objective of this study was to identify and characterise a subpopulation of human sarcoma-initiating cells. METHODS: We examined established rhabdomyosarcoma cell lines by flow cytometry. Tumourigenesis was examined by xenograft models. Real-time PCR and immunohistochemistry were performed to examine the gene expression using cell lines and biopsy specimens. RESULTS: Rhabdomyosarcoma cell lines included small populations of fibroblast growth factor receptor 3 (FGFR3)-positive cells. FGFR3-positive KYM-1 and RD cells were more strongly tumourigenic than FGFR3-negative cells. In addition, xenoengraftment of 33% of single FGFR3-positive KYM-1 cells yielded tumour formation. Stem cell properties of FGFR3-positive cells were further established by real-time PCR, which demonstrated upregulation of undifferentiated cell markers and downregulation of differentiation markers. We showed that in the absence of serum, addition of basic fibroblast growth factor maintained and enriched FGFR3-positive cells. On the other hand, ciliary neurotrophic factor reduced the proportion of FGFR3-positive cells. Real-time PCR and immunohistochemical examination revealed that embryonal rhabdomyosarcoma patient biopsy specimens were found to overexpress FGFR3. CONCLUSIONS: Our findings suggest that rhabdomyosarcoma cell lines include a minor subpopulation of FGFR3-positive sarcomainitiating cells, which can be maintained indefinitely in culture and which is crucial for their malignancy.

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“…Although PcG proteins are generally recognized as suppressors of target gene transcription, Shi et al reported that EZH2 enhances the transcription of c-myc and cyclin D1 (60). We previously found that transcription of c-myc is activated and expression of the ink4a locus are suppressed in osteosarcoma (61). These findings suggest that these genes may be targets of EZH2 and BMI-1 in osteosarcoma.…”

Section: Discussionmentioning

confidence: 80%

The knock-down of overexpressed EZH2 and BMI-1 does not prevent osteosarcoma growth

Sasaki

Setoguchi²,

Matsunoshita³

et al. 2010

Oncol Rep

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Abstract. Polycomb group proteins control the transcriptional memory of cells by maintaining the stable silencing of specific sets of genes through chromatin modifications. Polycomb group protein complexes control gene repression through recruitment of histone deacetylase. This recruitment leads to trimethylation of Lys 27 of histone H3 (H3K27). Histone H3K27 trimethylation is a property of stably silenced heterochromatin. EZH2 and BMI-1 are pivotal components of polycomb group protein complexes. Increased EZH2 levels have been found in several malignancies and reported as a molecular biomarker of poor prognosis. Similarly, BMI-1 has also been found to be associated with malignant transformation. In addition, inhibition of EZH2 or BMI-1 inhibits the growth of various types of malignancies. The expression of BMI-1 and EZH2 in human osteosarcoma has not been clearly determined. We examined the potential involvement of aberrant polycomb group protein expression in the pathogenesis of osteosarcoma. Real-time PCR revealed that expression of EZH2 in 143B, HOS, NOS-1 and Saos2 was increased compared to normal osteoblasts. BMI-1 was also up-regulated in 143B, HOS and NOS-1. Expression of EZH2 and BMI-1 were up-regulated in osteosarcoma patient biopsy specimens compared to normal bone. Immunohistochemical examinations showed that EZH2 and BMI-1 were up-regulated in osteosarcoma cells and that trimethylation of histone H3K27 was increased. We examined the effects of knock down of EZH2 and BMI-1 by shRNA. Unexpectedly, the knock-down of EZH2 and BMI-1 did not prevent osteosarcoma growth either in vitro or in vivo. Our findings suggest that EZH2 and BMI-1 may be tumorassociated antigens of osteosarcoma, but are not useful molecular targets of osteosarcoma treatment.

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Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation

Cited by 136 publications

References 39 publications

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

The knock-down of overexpressed EZH2 and BMI-1 does not prevent osteosarcoma growth

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