E6/E7 oncogenes in epithelial suprabasal layers and estradiol promote cervical growth and ear regeneration

Abstract

Tissue growth is a common characteristic of carcinogenesis and regeneration. Here we show that suprabasal expression of human papillomavirus (HPV)16 E6/E7 oncogenes in Tg(K6b-E6/E7) mice, similar to that observed in HPV-infected human tissue, and estradiol increased cervical epithelium growth and ear-hole closure efficiency. Oncogenes in combination with estradiol had a significant contribution to the proliferation of suprabasal cells of cervical epithelium that correlated with an increased expression of keratin genes. Remarkably, long-term treatments with estradiol resulted in evident cellular and tissue abnormalities indicative of a precancerous phenotype. Regenerating ear epithelium of transgenic mice also showed increased suprabasal cell proliferation and expression of keratin genes. Unexpectedly, we observed higher ear regeneration efficiency in adult than in young female mice, which was further increased by E6/E7 oncogenes. Supporting a role of estradiol in this phenomenon, ovariectomy and treatment with an estrogen receptor inhibitor caused a significant reduction in regenerative capacity. Our data suggest that Tg(K6b-E6/E7) mice are unique to mimic the initial stages of HPV-mediated cervical carcinogenesis, and ear regeneration could facilitate the elucidation of mechanisms involved.

Human Papillomavirus 11 Early Protein E6 Activates Autophagy by Repressing AKT/mTOR and Erk/mTOR

“…One possibility is that the ectopic expression of HPV11 E6 may increase the energy requirements and trigger metabolic stress, which is similar to the proposed outcome following the ectopic expression of HR-HPV16 E7 (41). Moreover, E6 can increase the numbers of unfolded and misfolded proteins in host cells (74), which activates autophagy. The increased autophagy levels could maintain host cell survival and help virus proliferation and expansion.…”

DNA viruses and cancer: insights from evolutionary biology

“…The suprabasal cell withdraws from the cell division cycle and undergoes a program of terminal differentiation, thus ensuring the mechanical stability of the skin and protecting the proliferating basal cells from direct exposure to environmental mutagens [48]. In order to establish a stable infection, PVs need to infect basal cells through mechanisms that remain poorly understood [16,17]. Following initial infection, the genomes are maintained at a low copy number in the basal cells and persistent infection is established.…”

“…The production of the infectious virus occurs in the terminally differentiated layers of the epithelium and progeny virions are sloughed off within the terminally differentiated, de-nucleated epithelial squames. The shed virus is stable and retains infectious properties over extended periods [16,17].…”