TRAF2 is an NF-κB-activating oncogene in epithelial cancers

Shen, Rhine R.; Zhou, Alicia Y.; Kim, Eejung; O’Connell, Joyce T.; Hägerstrand, Daniel; Beroukhim, Rameen; Hahn, William C.

doi:10.1038/onc.2013.543

Cited by 57 publications

(56 citation statements)

References 45 publications

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“…RANK adaptor molecules, TRAFs have been implicated in RANKL‐RANK signaling axis activating the downstream effectors of gene expression in osteoclasts (Asagiri & Takayanagi, ; Darnay et al, ; Wong et al, ). TRAF6 and TRAF2 have been linked to multiple myeloma and epithelial cancers respectively (Liu et al, ; Shen et al, ). Also space TRAF6 implicated in oncogenicity of OSCC tumors (Hung et al, ).…”

Section: Discussionmentioning

confidence: 99%

Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells

Sambandam

Ethiraj

Hathaway‐Schrader

et al. 2018

Journal Cellular Physiology

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Oral squamous cell carcinoma (OSCC) is the most common malignancy among oral cancers and shows potent activity for local bone invasion. Receptor activator of nuclear factor κB (RANK) ligand (RANKL) is critical for bone-resorbing osteoclast formation. We previously demonstrated that OSCC tumor cells express high levels of RANKL. In this study, confocal microscopy demonstrated RANKL specific receptor, RANK expression in OSCC tumor cell lines (SCC1, SCC12, and SCC14a). We also confirmed the expression of RANK and RANKL in primary human OSCC tumor specimens. However, regulatory mechanisms of RANKL expression and a functional role in OSCC tumor progression are unclear. Interestingly, we identified that RANKL expression is autoregulated in OSCC tumor cells. The RANKL specific inhibitor osteoprotegerin (OPG) treatment to OSCC cells inhibits autoregulation of RANKL expression. Further, we showed conditioned media from RANKL CRISPR-Cas9 knockout OSCC cells significantly decreased osteoclast formation and bone resorption activity. In addition, RANKL increases OSCC tumor cell proliferation. RANKL treatment to OSCC cells demonstrated a dose-dependent increase in RANK intracellular adaptor protein, TRAF6 expression, and activation of IKK and IκB signaling molecules. We further identified that transcription factor NFATc2 mediates autoregulation of RANKL expression in OSCC cells. Thus, our results implicate RANKL autoregulation as a novel mechanism that facilitates OSCC tumor cell growth and osteoclast differentiation/bone destruction.

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Section: Discussionmentioning

confidence: 99%

Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells

Sambandam

Ethiraj

Hathaway‐Schrader

et al. 2018

Journal Cellular Physiology

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“…Furthermore, TRAF2 has been identified as an oncogene that is amplified and rearranged in 15% of epithelial cancers. Knockdown of TRAF2 in multiple epithelial cancer cell lines harboring a TRAF2 copy number gain resulted in decreased cell proliferation and NF-B activation (61). This cumulative evidence indicates that the TRAF family of E3 ligases may be the most viable therapeutic target in NF-Bdriven malignancies.…”

Section: Nf-b Activationmentioning

confidence: 95%

The Emerging Role of Non-traditional Ubiquitination in Oncogenic Pathways

Dwane

Gallagher

Chonghaile

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe addition of ubiquitin to a target protein has long been implicated in the process of degradation and is the primary mediator of protein turnover in the cell. Recently, however, many non-proteolytic functions of ubiquitination have emerged as key regulators of cellular homeostasis. In this review, we will describe the various non-traditional functions of ubiquitination, with particular focus on how they can be used as signaling entities in cancer formation and progression. Elaboration of this topic can lead to a better understanding of oncogenic mechanisms, as well as the discovery of novel druggable proteins within the ubiquitin pathway.

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“…Activated TAK1/TAB2/3 complex phosphorylates and activates inhibitor of NF-kB kinase (IKK)-α/β/γ complex, finally giving rise to nuclear translocation and activation of NF-kB [32, 33]. As an adaptor protein of NF-kB signaling cascades, aberrant expression of TRAFs has been demonstrated to contribute to the constitutive activation of NF-kB signaling [46]. Silencing TRAF2 repressed PCa cell proliferation and tumorigenicity via inhibiting activation of NF-kB signaling in glioblastoma cells [47].…”

Section: Discussionmentioning

confidence: 99%

Decreased miR-218–5p Levels as a Serum Biomarker in Bone Metastasis of Prostate Cancer

Peng¹,

Chen

Wang

et al. 2019

Oncol Res Treat

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Background: miR-218–5p is an extensively studied microRNA (miRNA) in prostate cancer (PCa). However, the clinical significance and biological role of miR-218–5p in bone metastasis of PCa remain unclear. Materials and Methods: miR-218–5p expression was evaluated in 38 bone metastatic and 115 non-bone metastatic PCa tissues and serum samples. Clinical correlation of miR-218–5p expression with clinicopathological characteristics was analyzed. The biological roles of miR-218–5p in bone metastasis of PCa were investigated in vitro by invasion and migration assays. Bioinformatics analysis, real-time polymerase chain reaction, western blot, and luciferase reporter assay were applied to discern and examine the relationship between miR-218–5p and its potential targets. Results: miR-218–5p expression was reduced in bone metastatic PCa tissue and serum samples, which positively correlated with poor clinicopathological characteristics and bone metastasis-free survival in PCa patients. Upregulating miR-218–5p repressed PCa cell invasion and migration. Furthermore, miR-218–5p inhibited NF-κB signaling via simultaneously targeting TRAF1, TRAF2, and TRAF5, which suppressed the invasion and migration abilities of PCa cells. ROC curve analysis of miR-218–5p in the serum of PCa patients exhibited an area under the curve of 0.86 (95% confidence interval 0.80–0.92, p < 0.001). Conclusion: Our findings indicate that miR-218–5p might represent a novel serum biomarker for bone metastasis of PCa.

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TRAF2 is an NF-κB-activating oncogene in epithelial cancers

Cited by 57 publications

References 45 publications

Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells

Autoregulation of RANK ligand in oral squamous cell carcinoma tumor cells

The Emerging Role of Non-traditional Ubiquitination in Oncogenic Pathways

Decreased miR-218–5p Levels as a Serum Biomarker in Bone Metastasis of Prostate Cancer

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