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

Area of Science:

• Virology
• Molecular Biology
• Oncology

Background:

• Circular RNAs (circRNAs) are prevalent but largely uncharacterized.
• Virus-derived circRNAs have been identified in gamma-herpesviruses.
• The role of circRNAs in human papillomavirus (HPV) infections was unknown.

Purpose of the Study:

• To investigate the generation and function of circRNAs in oncogenic human papillomaviruses (HPVs).
• To determine if HPV-derived circRNAs can encode proteins and influence cancer progression.

Main Methods:

• Inverse RT-PCR and northern blotting to detect HPV16 circE7.
• N6-methyladenosine (m6A) modification analysis.
• Subcellular localization and polysome association studies.
• In vitro and in vivo experiments disrupting circE7 in cervical cancer cells.
• Analysis of TCGA RNA-Seq data.

Main Results:

• Oncogenic HPVs, including HPV16, generate circRNAs that encompass the E7 oncogene (circE7).
• HPV16 circE7 is N6-methyladenosine (m6A) modified, cytoplasmic, polysome-associated, and translated into E7 oncoprotein.
• Disrupting circE7 in CaSki cervical cancer cells reduced E7 protein levels and inhibited cancer cell growth.
• CircE7 was detected in HPV-positive cancer data and cell lines.

Conclusions:

• Virus-derived, protein-encoding circRNAs are biologically functional.
• HPV-generated circE7 contributes to the transforming properties of HPV and cancer cell proliferation.
• CircE7 represents a novel therapeutic target for HPV-associated cancers.