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OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways

  • Authors:
    • Jing Li
    • Chunhui Di
    • Jenny Jing
    • Qun Di
    • Jonathan Nakhla
    • David Cory Adamson

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  • Published online on: September 23, 2015     https://doi.org/10.3892/ijo.2015.3179
  • Pages: 1703-1710
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Abstract

The homeobox transcription factor orthodenticle homeobox 2 (OTX2) plays a critical role in very early neurogenesis, but can become oncogenic when aberrantly expressed later in life. We previously discovered its novel oncogenic role in the malignant childhood brain tumor medulloblastoma and hypothesize an oncogenic role in retinoblastoma. Primary retinoblastoma tumors and cell lines were analyzed by quantitative-PCR, immunoblotting and immunohistochemistry for OTX2. The effect of modulating OTX2 expression on tumorigenesis was tested pharmacologically and by siRNA. A lentiviral shRNA-engineered vector was used for conditional knockdown studies on tumor growth in vivo. A luciferase reporter assay was used to analyze ATRA's effect on OTX2's promoter. In this study on retinoblastoma, OTX2 was frequently amplified and/or overexpressed in primary tumors and cell lines. Knockdown of OTX2 expression by siRNA or pharmacologic inhibition by all-trans retinoic acid (ATRA) repressed OTX2 expression and cell proliferation and significantly decreased tumor growth in vivo. Loss of OTX2 expression also resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation. Aberrant expression of OTX2 may contribute to the development of retinoblastoma. OTX2 may serve as a common transcription factor that interlinks multiple tumor-driving pathways. These results also show that OTX2 can be genetically and pharmacologically targeted, providing an exciting new therapeutic option that may be less toxic and more efficacious than current treatments.
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November-2015
Volume 47 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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  • Journal Metrics
  • Impact Factor: 5.2
  • Ranked Oncology
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  • CiteScore: 11.4
  • CiteScore Rank: Q1: #40/366 Oncology
  • Source Normalized Impact per Paper (SNIP): 1.125
  • SCImago Journal Rank (SJR): 1.105
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Spandidos Publications style
Li J, Di C, Jing J, Di Q, Nakhla J and Adamson DC: OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways. Int J Oncol 47: 1703-1710, 2015
APA
Li, J., Di, C., Jing, J., Di, Q., Nakhla, J., & Adamson, D.C. (2015). OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways. International Journal of Oncology, 47, 1703-1710. https://doi.org/10.3892/ijo.2015.3179
MLA
Li, J., Di, C., Jing, J., Di, Q., Nakhla, J., Adamson, D. C."OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways". International Journal of Oncology 47.5 (2015): 1703-1710.
Chicago
Li, J., Di, C., Jing, J., Di, Q., Nakhla, J., Adamson, D. C."OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways". International Journal of Oncology 47, no. 5 (2015): 1703-1710. https://doi.org/10.3892/ijo.2015.3179