Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus

Nat Commun. 2019 May 24;10(1):2300. doi: 10.1038/s41467-019-10246-5.

Abstract

Single-stranded circular RNAs (circRNAs), generated through 'backsplicing', occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology*
  • Datasets as Topic
  • Female
  • Gene Knockdown Techniques
  • Host-Pathogen Interactions / genetics*
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / pathogenicity
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Papillomavirus E7 Proteins / genetics
  • Polyribosomes / genetics
  • Polyribosomes / metabolism
  • RNA / genetics
  • RNA / isolation & purification
  • RNA / metabolism*
  • RNA, Circular
  • RNA, Small Interfering / metabolism
  • RNA, Viral / genetics
  • RNA, Viral / isolation & purification
  • RNA, Viral / metabolism*
  • Sequence Analysis, RNA
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*
  • Xenograft Model Antitumor Assays

Substances

  • Papillomavirus E7 Proteins
  • RNA, Circular
  • RNA, Small Interfering
  • RNA, Viral
  • RNA