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Detection of human papillomavirus in human focal cortical dysplasia type IIB.
- Source :
-
Annals of neurology [Ann Neurol] 2012 Dec; Vol. 72 (6), pp. 881-92. - Publication Year :
- 2012
-
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.<br />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.<br />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.<br />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.<br /> (Copyright © 2012 American Neurological Association.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1531-8249
- Volume :
- 72
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Annals of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 23280839
- Full Text :
- https://doi.org/10.1002/ana.23795