Quickly by accumulating additional genetic lesions and/orĮpigenetic changes in key cancer pathways ( 3). Retinoblastoma tumor suppressor gene ( RB1) and progresses Tumor is often initiated by the biallelic loss of the Retinoblastoma affects ~1 in 18,000Ĭhildren and can become fatal if left untreated ( 1, 3, 4). Intraocular tumor in children, typically occurring before 5 years Retinoblastoma is the most common malignant 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. OTX2 may serve as a common transcription factor that interlinks multiple tumor-driving pathways. Aberrant expression of OTX2 may contribute to the development of retinoblastoma. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation. Loss of OTX2 expression also resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. 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. In this study on retinoblastoma, OTX2 was frequently amplified and/or overexpressed in primary tumors and cell lines. A luciferase reporter assay was used to analyze ATRA's effect on OTX2's promoter. A lentiviral shRNA-engineered vector was used for conditional knockdown studies on tumor growth in vivo. The effect of modulating OTX2 expression on tumorigenesis was tested pharmacologically and by siRNA. Primary retinoblastoma tumors and cell lines were analyzed by quantitative-PCR, immunoblotting and immunohistochemistry for OTX2. We previously discovered its novel oncogenic role in the malignant childhood brain tumor medulloblastoma and hypothesize an oncogenic role in retinoblastoma. 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.
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