Abstract
Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.
Highlights
Papillomaviruses and their host species have evolved together for tens of millions of years, and it is thought that the viruses have both adapted to specific host niches and co-speciated with their hosts [1]
Genome Atlas (TCGA), we found that with respect to repressed genes, Human papillomavirus (HPV)-positive and HPV-negative cancers differ primarily in gene sets related to epithelial differentiation
Basal keratins, such as keratin 5, are relatively unaffected by HPV16 E6 and E7, but HPV16 E7 tends to downregulate individual genes related to epithelial differentiation and a similar effect is observed with HPV16 E6 alone or with HPV16 E6 and E7 expressed together [110]
Summary
Papillomaviruses and their host species have evolved together for tens of millions of years, and it is thought that the viruses have both adapted to specific host niches and co-speciated with their hosts [1]. To enable viral genome replication in infected epithelial cells that would have otherwise committed to a terminal differentiation program, the virus must promote proliferation in the differentiating cell. This is said to ‘uncouple’ proliferation from differentiation. Some of the pro-proliferative mechanisms employed by HPV E6 and E7 are shared by other DNA tumor viruses that do not infect stratified epithelia. This review will summarize the studies that have established the effects of HPV-encoded proteins, HPV E6 and E7, on epithelial differentiation It will highlight some of the mechanisms by which HPV E6 and E7 delay and impair differentiation. Open questions related to HPV control of epithelial differentiation and the possibility of differentiation therapy for HPV-positive cancers will be discussed
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