Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including <i>VEGFA</i>, in human osteosarcoma

Yang, Jilong; Yang, Da; Sun, Yan; Sun, Bei; Wang, Guowen; Trent, Jonathan C.; Araujo, Dejka M.; Chen, Kexin; Zhang, Wei

doi:10.1002/cncr.26116

Cited by 108 publications

(111 citation statements)

References 39 publications

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“…This pattern of copy number alterations was strikingly similar to that from an independent aCGH dataset (GSE9654) of osteosarcoma samples obtained from Canadian patients [2,3,11]. It was therefore reasonable to pool the two aCGH datasets (GSE19180 and GSE 9654) for further pathway analysis.…”

Section: Resultssupporting

confidence: 63%

The genetic basis for inactivation of Wnt pathway in human osteosarcoma

Yang

et al. 2014

BMC Cancer

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BackgroundOsteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma.MethodsaCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, β-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples.ResultsKEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no β-catenin protein was detected in the nucleus. β-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall survival of human osteosarcoma patients.ConclusionsFrequent deletions of Wnt and other Wnt signaling pathway genes suggest that the Wnt signaling pathway is genetically inactivated in human osteosarcoma.

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Section: Resultssupporting

confidence: 63%

The genetic basis for inactivation of Wnt pathway in human osteosarcoma

Yang

et al. 2014

BMC Cancer

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“…85,88,94,98,104,114,117–125 Collectively, the finding that near ubiquitous alterations in the Rb and p53 pathway function in osteosarcoma through both gain- and loss-of-function mutations indicates that loss of cell cycle control and inappropriate DNA damage response are key drivers of osteosarcoma development. The role that these genetic alterations play in tumor progression and metastasis, however, remains less clear.…”

Section: Geneticsmentioning

confidence: 99%

Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

2015

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Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation.

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“…A better understanding of the underlying mechanism of the carcinogenesis of osteosarcoma is crucial for the diagnosis of and the treatment for osteosarcoma. A variety of signaling pathways, such as hedgehog [3], vascular endothelial growth factor (VEGF) [4, 5], platelet-derived growth factor (PDGF) [6], Wnt [7] and signal transducer and activator of transcription (STAT) pathways [8], have been demonstrated to mediate cell proliferation, apoptosis or invasion of osteosarcoma cells.…”

Section: Introductionmentioning

confidence: 99%

Serine/Threonine Kinase 35, a Target Gene of STAT3, Regulates the Proliferation and Apoptosis of Osteosarcoma Cells

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serine/threonine kinase 35 (STK35) may be associated with Parkinson disease and human colorectal cancer, but there have been no reports on the expression levels or roles of STK35 in osteosarcoma. Methods: STK35 mRNA expression was determined in osteosarcoma and bone cyst tissues by real-time PCR. Cell proliferation and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, respectively. Results: STK35 was up-regulated in osteosarcoma tissues as indicated by analyzing publicly available expression data (GEO dataset E-MEXP-3628) and real-time PCR analysis on our own cohort. We subsequently investigated the effects of STK35 knockdown on two osteosarcoma cell lines, MG63 and U2OS. STK35 knockdown inhibited the growth of osteosarcoma cells in vitro and in xenograft tumors. Meanwhile, STK35 knockdown enhanced apoptosis. Expression of the active forms and the activity of two major executioner caspases, caspase 3 and caspase 7, were also increased in osteosarcoma cells with STK35 silenced. Additionally, Gene Set Enrichment Analysis (GSEA) identified that the JAK/STAT signaling pathway was positively correlated with STK35 expression. The mRNA expression of STK35 was repressed by STAT3 small interfering RNA (siRNA), but not by siRNA of STAT4, STAT5A or STAT6. A luciferase reporter assay further demonstrated that STAT3 transcriptionally regulated STK35 expression. A chromatin immunoprecipitation (ChIP) assay confirmed the direct recruitment of STAT3 to the STK35 promoter. The promotion effects of STAT3 knockdown on cell apoptosis were partially abolished by STK35 overexpression. Furthermore, STK35 mRNA expression was positively correlated with STAT3 mRNA expression in osteosarcoma tissues by Pearson correlation analysis. Conclusions: These results collectively reveal that STAT3 regulates the transcription of STK35 in osteosarcoma. STK35 may exert an oncogenic role in osteosarcoma.

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Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma

Cited by 108 publications

References 39 publications

The genetic basis for inactivation of Wnt pathway in human osteosarcoma

The genetic basis for inactivation of Wnt pathway in human osteosarcoma

Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

Serine/Threonine Kinase 35, a Target Gene of STAT3, Regulates the Proliferation and Apoptosis of Osteosarcoma Cells

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