RUNX3 Facilitates Growth of Ewing Sarcoma Cells

Bledsoe, Krista L.; McGee‐Lawrence, Meghan E.; Camilleri, Emily T.; Wang, Xiaoke; Riester, Scott M.; Wijnen, André J. van; Oliveira, André M.

doi:10.1002/jcp.24663

Cited by 16 publications

(12 citation statements)

References 46 publications

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“…While there has been a profusion of publications describing the role of RUNX3 as a tumor suppressor in a large variety of human cancers, the role of RUNX3 as an oncogene and the mechanisms of RUNX3 upregulation are poorly understood. 9 , 10 , 11 , 12 , 34 , 36 Notably, we have demonstrated in this study that the oncogenic role of RUNX3 is transcriptionally regulated by MYC in NKTL. This is in line with data implicating the RUNX genes as MYC collaborating genes whereby RUNX targeting by retroviruses in T- or B-lymphoid cells have been identified in transgenic models harboring MYC.…”

Section: Discussionmentioning

confidence: 51%

“…In the recent years, there is increasing recognition that RUNX3 can also act as an oncogene in skin cancers including basal cell carcinomas (BCC), ovarian cancers, squamous cell carcinomas (SCC) of the head and neck, and Ewing sarcoma. 9 , 10 , 11 , 12 , 34 , 35 , 36 Moreover, high level expression of RUNX3 has been correlated with poor prognosis in a subset of acute myeloid leukemia carrying FLT3 mutations. 37 In BCC and SCC of head and neck, the overexpressed RUNX3 proteins are full-length and intact without mutation and fully functional.…”

Section: Discussionmentioning

confidence: 99%

“… 9 RUNX3 is also oncogenic in head and neck squamous cell carcinoma, ovarian cancer and Ewing sarcoma where overexpression of RUNX3 promoted proliferation and tumorigenesis. 10 , 11 , 12 Collectively, these findings suggest that RUNX3 can function as an oncogene and tumor suppressor in a cellular context-dependent manner.…”

Section: Introductionmentioning

confidence: 89%

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RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

et al. 2017

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RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

et al. 2017

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“…Later its oncogenic behavior was verified in basal cell carcinoma with overexpressed RUNX3 in cancers compared to the normal epidermis ( 27 ). Likewise, RUNX3 overexpression is observed to increase proliferation and tumorigenesis in ovarian cancer, head, and neck squamous cell carcinoma and Ewing sarcoma ( 18 , 28 , 29 ). All these observations suggest the cell type and contextual-dependent behavior of RUNX3 as a tumor suppressor or a promoter.…”

Section: Runx3 In Tumorigenesismentioning

confidence: 99%

Emerging role of RUNX3 in the regulation of tumor microenvironment

Manandhar

Lee

2018

BMB Rep.

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A number of genes have been therapeutically targeted to relieve cancer, but cancer relapse is still a growing issue. The concept that the surrounding tumor environment is critical for the progression of cancer may foster an answer to the issue of cancer malignancy. Runt domain transcription factors (RUNX1, 2, and 3) are evolutionarily conserved and have been intensively studied for their roles in normal development and pathological conditions. During tumor growth, a hypoxic microenvironment and infiltration of the tumor by immune cells are common phenomena. In this review, we briefly introduce the consequences of hypoxia and immune cell infiltration into the tumor microenvironment with a focus on RUNX3 as a critical regulator. Furthermore, based on our current knowledge of the functional role of RUNX3 in hypoxia and immune cell maintenance, a probable therapeutic intervention is suggested for the effective management of tumor growth and malignancy.

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“…The fusion oncoprotein EWS/FLI1 t(11;p22)(q24;q12) (Ewing's sarcoma; Fos-like immunoreactivity; Finkel osteosarcoma retroviral oncogene; Friend leukemia insertion; here: Friend leukemia insertion at 11q24.3) binds RUNX2 and prevents its action. Runx3 protein promoted oncoprotein EWS/FLI-stimulated target gene responses, and Runx2 and transcriptional co-activator core binding factor-β (CBFβ) promote invasiveness ( 98 ). Runx2 and bone morphogenetic protein (BMP, member of TGFβ family) upregulated snail-induced lung cancer cell migration and epithelial-to-mesenchymal transition ( 99 ).…”

Section: The Primordial Cell Survival Pathways Become Proto-oncogementioning

confidence: 99%

The cnidarian origin of the proto-oncogenes NF-κB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review)

Sinkovics

2015

Int J Oncol

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The cell survival pathways of the diploblastic early multicellular eukaryotic hosts contain and operate the molecular machinery resembling those of malignantly transformed individual cells of highly advanced multicellular hosts (including Homo). In the present review, the STAT/NF-κB pathway of the cnidarian Nematostella vectensis is compared with that of human tumors (malignant lymphomas, including Reed-Sternberg cells) pointing out similarities, including possible viral initiation in both cases. In the ctenophore genome and proteome, β-catenin gains intranuclear advantages due to a physiologically weak destructive complex in the cytoplasm, and lack of natural inhibitors (the Dickkopfs). Thus, a scenario similar to what tumor cells initiate and achieve is presented through several constitutive loss-of-function type mutations in the destructive complex and in the elimination of inhibitors. Vice versa, malignantly transformed individual cells of advanced multicellular hosts assume pheno-genotypic resemblance to cells of unicellular or early multicellular hosts, and presumably to their ancient predecessors, by returning to the semblance of immortality and to the resumption of the state of high degree of resistance to physicochemical insults. Human leukemogenic and oncogenic pathways are presented for comparisons. The supreme bioengineers RNA/DNA complex encoded both the malignantly transformed immortal cell and the human cerebral cortex. The former generates molecules for the immortality of cellular life in the Universe. The latter invents the inhibitors of the process in order to gain control over it.

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RUNX3 Facilitates Growth of Ewing Sarcoma Cells

Cited by 16 publications

References 46 publications

RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

Emerging role of RUNX3 in the regulation of tumor microenvironment

The cnidarian origin of the proto-oncogenes NF-κB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review)

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