Detection of human papillomavirus in human focal cortical dysplasia type IIB

Ann Neurol. 2012 Dec;72(6):881-92. doi: 10.1002/ana.23795.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Brain / metabolism*
  • Brain / virology
  • Brain Diseases / etiology
  • Brain Diseases / pathology*
  • 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 / pathology*
  • 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
  • Oncogene Proteins, Viral / metabolism*
  • RNA, Messenger / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Young Adult

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • E6 protein, Human papillomavirus type 18
  • Multiprotein Complexes
  • Oncogene Proteins, Viral
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1

Supplementary concepts

  • Focal cortical dysplasia of Taylor