Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression

Tsuru, Arisa; Setoguchi, Takao; Matsunoshita, Yukihiro; Nagao‐Kitamoto, Hiroko; Nagano, Satoshi; Yokouchi, Masahiro; Maeda, Shingo; Ishidou, Yasuhiro; Yamamoto, Takuya; Komiya, Setsuro

doi:10.1038/bjc.2015.84

Cited by 32 publications

(26 citation statements)

References 45 publications

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“…All of these studies showed that OS cells with higher metastatic potential have higher basal levels of notch receptors, especially notch-1, notch-2, notch ligands (Dll-1/Jagged-1), and notch target genes such as hey-1 and hes-1, as compared to normal osteoblasts or non-metastatic OS cell lines. Higher expression levels of these notch signaling associated genes or proteins were shown to be involved in invasiveness and metastasis and thus in impacting OS patient survival [16, 17]. Increased levels of jagged-1 in OS cells promote bone metastasis by activating stromal notch signaling.…”

Section: Signaling Pathwaysmentioning

confidence: 99%

“…Therefore, abolishing expression of hey-1, hes-1, notch-1, and jagged-1 by using γ-secretase inhibitors (GSI) also abolished their direct/indirect effects on survival, bone metastasis, and invasiveness in OS [16, 18]. These findings suggest that inhibiting notch signaling at various points may be a novel therapeutic strategy for preventing OS invasiveness and metastasis [17]. …”

Section: Signaling Pathwaysmentioning

confidence: 99%

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Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

et al. 2017

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Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, including Notch, Wnt, Hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, and JAK/STAT, and their specific role in osteosarcoma. In addition, we highlight numerous natural compounds that have been documented to target these pathways effectively, including curcumin, diallyl trisulfide, resveratrol, apigenin, cyclopamine, and sulforaphane. We elucidate through references that these natural compounds can induce cancer signaling pathway manipulation and possibly facilitate new treatment modalities for osteosarcoma.

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Section: Signaling Pathwaysmentioning

confidence: 99%

Section: Signaling Pathwaysmentioning

confidence: 99%

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

et al. 2017

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“…Subsequently, Hey proteins were found to be involved in tumor metastasis progression. In vitro, Hey1 knockdown inhibited the invasive phenotype of osteosarcoma via downregulation of MMP9 (16). Furthermore, the transfection of Hey1 antisense oligonucleotides blocked EMT through E-cadherin expression, and Smad3 inhibition repressed Hey1-induced EMT phenotype even in the presence of TGFb (30).…”

Section: The Roles Of Hey Proteins In Cancer Metastasismentioning

confidence: 92%

“…However, the fact that HeyL differs in one of the key motifs, namely the YHSW motif, from Hey1 and Hey2 which both have the YRPW motif, may be one of the reasons why it acts differently from other Hey proteins. While YRPW appears to be a good target (16), YHSW, at least in hepatocellular carcinoma, may not be. This is clearly a fascinating area to explore, both in research and in clinical settings.…”

Section: The Roles Of Hey Proteins In Cancer Metastasismentioning

confidence: 99%

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Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

et al. 2017

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Dysregulation of sirtuin 6 (SIRT6) is actively involved in tumor progression. High levels of SIRT6 have been associated with hepatocellular carcinoma and non‐small cell lung cancer, and SIRT6 facilitates growth and metastasis of cancer cells. However, the clinical significance and biological function of SIRT6 are not known for osteosarcoma (OS). Here, we report that SIRT6 was notably overexpressed in OS tissues compared with non‐cancerous specimens. The high level of SIRT6 was prominently correlated with malignant clinical parameters and poor prognosis of OS patients. SIRT6 was also up‐regulated in OS cells. SIRT6 knockdown inhibited the invasion and migration of Saos‐2 and U2OS cells in vitro , while SIRT6 restoration increased these cellular biological behaviors in MG‐63 cells. Mechanistically, SIRT6 up‐regulated expression of matrix metallopeptidase 9 (MMP9) in OS cells. MMP9 restoration partially abolished the effects of SIRT6 knockdown on OS cells, with increased cell migration and invasion. MMP9 knockdown reduced migration and invasion of SIRT6‐overexpressing MG‐63 cells. Furthermore, SIRT6 positively modulated the levels of phosphorylated extracellular signal‐regulated kinases 1 and 2 (ERK1/2). PD098059 and PD0325901, inhibitors of mitogen‐activated protein kinase kinase (MEK), blocked the regulatory effects of SIRT6 on p‐ERK1/2 and MMP9 levels, suggesting that SIRT6 regulated MMP9 abundance probably through the MEK–ERK1/2 pathway. These results suggest that SIRT6 may act as a prognostic predictor and a drug target for OS patients.

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Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression

Cited by 32 publications

References 45 publications

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

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