NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma

Zhao, Sibo; Kurenbekova, Lyazat; Gao, Ying; Roos, Alison; Creighton, Chad J.; Rao, Pulivarthi H.; Hicks, John; Man, Tsz-Kwong; Lau, Ching C.; Brown, Anthony M.; Jones, Stephen N.; Lazar, Alexander J.; Ingram, Davis R.; Lev, Dina; Donehower, Lawrence A.; Yustein, Jason T.

doi:10.1038/onc.2014.429

Cited by 107 publications

(107 citation statements)

References 47 publications

(41 reference statements)

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“…Among the most frequently mutated genes in our present study, NKD2 is a negative regulator of Wnt/β‐catenin signalling and suppresses tumour growth and metastasis in osteosarcoma 33. Nuclear receptor corepressors (Ncors) are important for developmental and homoeostatic processes in vertebrates.…”

Section: Discussionmentioning

confidence: 87%

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Guo

Wang

et al. 2017

J Cellular Molecular Medi

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Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole‐exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.

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Section: Discussionmentioning

confidence: 87%

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Guo

Wang

et al. 2017

J Cellular Molecular Medi

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“…Therefore, a more detailed understanding of the pathophysiological mechanisms in OS metastasis is necessary for the development of novel treatment strategies to improve the prognosis for OS patients with metastatic disease. Although several evolutionary signaling pathways have been demonstrated to be associated with OS pathogenesis, including the Wnt, Notch, mechanistic target of rapamycin and PI3K/Akt signaling pathways (19)(20)(21)(22), the molecular mechanisms of OS metastases have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Blocking fatty acid synthase inhibits tumor progression of human osteosarcoma by regulating the human epidermal growth factor receptor 2/phosphoinositide 3-kinase/protein kinase B signaling pathway in xenograft models

Chen

Ruan

Long

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated that fatty acid synthase (FASN) is overexpressed in osteosarcoma (OS) cells and tissues and, therefore, knockdown of FASN may inhibit OS cell proliferation, migration and invasion via regulation of the human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K)/protein kinase B(Akt) signaling pathway in vitro. However, the tumor microenvironment has a crucial role in the determination of tumor malignant phenotype. The aim of the present study was to investigate the effect of knockdown of FASN on OS progression and the potential molecular mechanism in nude mice with orthotopic tumor implants in vivo. Results demonstrated that the knockdown of FASN markedly suppressed the growth and metastasis of OS, at least partially, by blocking the HER2/PI3K/Akt signal pathway in mice with intratibial 143B OS xenografts. These results suggest that the FASN/HER2/PI3K/Akt signaling pathway may be a potential therapeutic target for OS management.

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“…Specifically, using insights gained from our genetically engineered mouse model (GEMM) of metastatic OS and correlative human studies, we have identified aberrant expression of sFRP2 in metastatic osteosarcoma [15]. The dysregulation of sFRP2 has been reported in several malignancies, however the mechanisms by which it contributes to the biology of these cancers has been variable.…”

Section: Introductionmentioning

confidence: 99%

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

et al. 2016

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BackgroundOsteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated.MethodsStudies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. ResultsFunctional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development.ConclusionsWhile future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2909-6) contains supplementary material, which is available to authorized users.

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NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma

Cited by 107 publications

References 47 publications

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Multi‐genic pattern found in rare type of hypopituitarism: a whole‐exome sequencing study of Han Chinese with pituitary stalk interruption syndrome

Blocking fatty acid synthase inhibits tumor progression of human osteosarcoma by regulating the human epidermal growth factor receptor 2/phosphoinositide 3-kinase/protein kinase B signaling pathway in xenograft models

Secreted Frizzled-Related Protein 2 (sFRP2) promotes osteosarcoma invasion and metastatic potential

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