Human Papillomavirus E6/E7 Oncogenes Promote Mouse Ear Regeneration by Increasing the Rate of Wound Re-epithelization and Epidermal Growth

Abstract

Mammals have limited regeneration capacity. We report here that, in transgenic mice (Tg(bK6-E6/E7)), the expression of the E6/E7 oncogenes of human papilloma virus type 16 (HPV16) under the control of the bovine keratin 6 promoter markedly improves the mouse's capacity to repair portions of the ear after being wounded. Increased repair capacity correlates with an increased number of epidermal proliferating cells. In concordance with the expected effects of the E6 and E7 oncogenes, levels of p53 decreased and those of p16 in epidermal cells increased. In addition, we observed that wound re-epithelization proceeded faster in transgenic than in wild-type animals. After the initial re-epithelization, epidermal cell migration from the intact surrounding tissue appears to be a major contributor to the growing epidermis, especially in the repairing tissue of transgenic mice. We also found that there is a significantly higher number of putative epidermal stem cells in Tg(bK6-E6/E7) than in wild-type mice. Remarkably, hair follicles and cartilage regenerated within the repaired ear tissue, without evidence of tumor formation. We propose that the ability to regenerate ear portions is limited by the capacity of the epidermis to repair itself and grow.

Silver Nanoparticles Mediate Differential Responses in Keratinocytes and Fibroblasts during Skin Wound Healing

“…A few studies of wound-healing events have shown that many drugs can promote wound healing by accelerated re-epithelialization through enhanced keratinocyte migration and proliferation. [20][21][22][23] In our study, we initially focused on keratinocytes to investigate the morphological changes mediated by AgNPs. In agreement with the results of others, our histological findings demonstrate that AgNPs do indeed promote the proliferation and migration of keratinocytes from wound edge toward the wound center.…”

Induction of focal epithelial hyperplasia in tongue of young bk6-E6/E7 HPV16 transgenic mice

“…After the initial re-epithelization, epidermal cell migration from the intact surrounding tissue appears to be a major contributor to the growing epidermis, especially in the repairing tissue of transgenic mice. We also found that there is a significantly higher number of putative epidermal stem cells in Tg(bK6-E6/E7) than in wild-type mice (Valencia et al 2008).…”

“…The construction of transgenic mice containing the HPV16 E6/E7 viral oncogenes under the promoter of the bovine keratin 6 gene (Tg[bK6-E6/E7] mice), their propagation, the expression of the viral oncogenes and the skin phenotype was already described (Escalante-Alcalde et al 2000;Valencia et al 2008). Mice were housed and treated according to the American Association of Laboratory Animal Care (AALAC) regulations.…”

“…Viral transcripts were abundant in the tongue, female reproductive tract and skin of these mice; the outer root sheath of hair follicles of Tg[bK6-E6/E7] expressing the viral oncogenes extends the growth phase and bypasses resting at telogen (Escalante-Alcalde et al 2000). In addition, we have observed that wound re-epithelization proceeded faster in transgenic than in wild-type animals (Valencia et al 2008). After the initial re-epithelization, epidermal cell migration from the intact surrounding tissue appears to be a major contributor to the growing epidermis, especially in the repairing tissue of transgenic mice.…”

The role of human papillomaviruses in cancer progression

“…[22,23,69] In low-risk HPV types, the wound healing process may hold an important role in the initial proliferation of the infected cells. [70] For the highrisk HPV types, viral proteins E6 and E7 function in the cell proliferation in the basal and parabasal cell layers. This function is particularly important at cervical sites where neoplasias may occur.…”