1. Detection of human papillomavirus in human focal cortical dysplasia type IIB.
- Author
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Chen J, Tsai V, Parker WE, Aronica E, Baybis M, and Crino PB
- Subjects
- Adolescent, Adult, Aged, Animals, Brain virology, Brain Diseases etiology, Brain Diseases virology, Cell Line, Tumor, Child, Child, Preschool, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA-Binding Proteins, Disease Models, Animal, Electroporation, Embryo, Mammalian, Embryonic Stem Cells metabolism, Embryonic Stem Cells virology, Epilepsy, Female, Gene Expression Regulation, Viral physiology, HIV Infections complications, HIV Infections genetics, HIV Infections metabolism, Humans, Infant, Male, Malformations of Cortical Development etiology, Malformations of Cortical Development virology, Malformations of Cortical Development, Group I, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Middle Aged, Multiprotein Complexes metabolism, Oncogene Proteins, Viral genetics, RNA, Messenger metabolism, TOR Serine-Threonine Kinases metabolism, Uterine Cervical Neoplasms pathology, Young Adult, Brain metabolism, Brain Diseases pathology, Malformations of Cortical Development pathology, Oncogene Proteins, Viral metabolism
- Abstract
Objective: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens., Methods: HPV16 E6 protein expression was assayed by immunohistochemistry in FCDIIB specimens (n = 50) and control brain specimens (n = 36). HPV16 E6 DNA was assayed by polymerase chain reaction (PCR) and in situ hybridization; HPV16 E6 mRNA was assayed by reverse transcriptase PCR. HPV16 E6 was transfected into fetal mouse brains by in utero electroporation to test the effects of E6 on cortical development., Results: HPV16 E6 protein was robustly expressed in all FCDIIB specimens in BCs, but not in regions without BCs or in control tissue specimens including normal brain, lymphoblasts, and fibroblasts, cortical tubers, and U87 glioma cells. E6 expression in FCDIIB colocalized with phosphoactivated S6 protein, a known mTORC1 substrate. HPV16 E6 DNA and mRNA were detected in representative specimens of FCDIIB but not control cortex, and were confirmed by sequencing. Transfection of E6 into fetal mouse brains caused a focal cortical malformation in association with enhanced mTORC1 signaling., Interpretation: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development., (Copyright © 2012 American Neurological Association.)
- Published
- 2012
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