Research Papers:

RD3 loss dictates high-risk aggressive neuroblastoma and poor clinical outcomes

Faizan H. Khan, Vijayabaskar Pandian, Satish Kumar Ramraj, Sheeja Aravindan, Mohan Natarajan, Seifollah Azadi, Terence S. Herman and Natarajan Aravindan _

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Oncotarget. 2015; 6:36522-36534. https://doi.org/10.18632/oncotarget.5204

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Faizan H. Khan1,*, Vijayabaskar Pandian1,*, Satish Kumar Ramraj1,*, Sheeja Aravindan2, Mohan Natarajan3, Seifollah Azadi4, Terence S. Herman1,2, Natarajan Aravindan1

1Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

2Stephenson Cancer Center, Oklahoma City, OK, USA

3Department of Pathology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA

4Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

*These authors have contributed equally to this work

Correspondence to:

Natarajan Aravindan, e-mail: [email protected]

Keywords: RD3, neuroblastoma, tumor suppressor, high-risk aggressive neuroblastoma, metastasis

Received: July 28, 2015     Accepted: August 28, 2015     Published: September 08, 2015


Clinical outcomes for high-risk neuroblastoma patients remains poor, with only 40–50% 5-Year overall survival (OS) and <10% long-term survival. The ongoing acquisition of genetic/molecular rearrangements in undifferentiated neural crest cells may endorse neuroblastoma progression. This study recognized the loss of Retinal Degeneration protein 3, RD3 in aggressive neuroblastoma, and identified its influence in better clinical outcomes and defined its novel metastasis suppressor function. The results showed ubiquitous expression of RD3 in healthy tissues, complete-loss and significant TNM-stage association of RD3 in clinical samples. RD3-loss was intrinsically associated with reduced OS, abridged relapse-free survival, aggressive stage etc., in neuroblastoma patient cohorts. RD3 was transcriptionally and translationally regulated in metastatic site-derived aggressive (MSDAC) cells (regardless of CSC status) ex vivo and in tumor manifolds from metastatic sites in reproducible aggressive disease models in vivo. Re-expressing RD3 in MSDACs reverted their metastatic potential both in vitro and in vivo. Conversely muting RD3 in neuroblastoma cells not only heightened invasion/migration but also dictated aggressive disease with metastasis. These results demonstrate the loss of RD3 in high-risk neuroblastoma, its novel, thus-far unrecognized metastasis suppressor function and further imply that RD3-loss may directly relate to tumor aggressiveness and poor clinical outcomes.

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