Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.
Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.
Di
Chunhui
C
Brain Tumor Center, Department of Pathology, Duke University Medical Center, Research Drive, Durham, NC 27710, USA.
Liao
Shaoxi
S
Adamson
David C
DC
Parrett
Timothy J
TJ
Broderick
Daniel K
DK
Shi
Qun
Q
Lengauer
Christoph
C
Cummins
Jordan M
JM
Velculescu
Victor E
VE
Fults
Daniel W
DW
McLendon
Roger E
RE
Bigner
Darell D
DD
Yan
Hai
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005784:Gene Amplification; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics; D051857:Otx Transcription Factors; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014212:Tretinoin