Telomerase Induction in HPV Infection and Oncogenesis

Abstract

Telomerase extends the repetitive DNA at the ends of linear chromosomes, and it is normally active in stem cells. When expressed in somatic diploid cells, it can lead to cellular immortalization. Human papillomaviruses (HPVs) are associated with and high-risk for cancer activate telomerase through the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). The expression of hTERT is affected by both high-risk HPVs, E6 and E7. Seminal studies over the last two decades have identified the transcriptional, epigenetic, and post-transcriptional roles high-risk E6 and E7 have in telomerase induction. This review will summarize these findings during infection and highlight the importance of telomerase activation as an oncogenic pathway in HPV-associated cancer development and progression.

Keywords: HPV E6; HPV E7; cancer; hTERT; human papillomavirus; oncogenic virus; papillomaviruses; telomerase.

Figure 1

HPV infection and telomerase induction. Telomerase, and its rate determining catalytic subunit, hTERT, is normally not expressed in somatic cells. With a HR HPV infection, E6 and E7 activate the hTERT gene. With disease progression, hTERT activation and telomerase activity increases (demonstrated by darker, larger arrows), and the expression of HR E6 and E7 also increases with the integration of HPV DNA into the host cell chromosomal DNA or loss of E2 regulation. LGSIL (low-grade squamous intraepithelial lesion) is typical for an active HPV infection. HGSIL (high-grade squamous intraepithelial lesion) is typical for a HR HPV infection with worsening cytologic changes and parallel greater histologic involvement, with multiple layers of the stratified squamous epithelium. CIN2/3 (cervical intraepithelial neoplasia 2 or 3) shows histologic changes due to an active HPV infection that involved most (2) or all (3) of the stratified squamous epithelium. Carcinoma in situ is the full thickness involvement of stratified squamous epithelium without breakdown of the basement membrane.