Abstract
Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomically diverse regions, and the majority of cervical intraepithelial neoplasia and cancers arise within the cervical squamo-columnar junction where undifferentiated basal progenitor cells with stem cell properties are found. The cancer stem cell theory particularly associates tumorigenesis, invasion, dissemination, and metastasis with cancer cells exhibiting stem cell properties. In this perspective, we discuss evidence of a cervical cancer stem cell niche and explore the association of stemness related genes with 5-year survival using a publicly available transcriptomic dataset of a cervical cancer cohort. We report that poor prognosis in this cohort correlates with overexpression of a subset of stemness pathway genes, a majority of which regulate the central Focal Adhesion pathway, and are also found to be enriched in the HPV infection pathway. These observations support therapeutic targeting of stemness genes overexpressed by mucosal cells infected with high-risk HPVs.
Highlights
TO HPV VIROLOGY AND DISEASEOncogenic human papillomavirus (HPV) infections are responsible for 5% of the global human cancer burden, resulting in over 634,000 new cancers annually, of which ∼90% are in women (Schiffman et al, 2016)
The majority of these genes belonged to the Focal Adhesion pathway, but we identified genes of other stemnessrelated pathways including Notch, Hippo, Wnt, and Hedgehog, and many of these gene products signal across pathways (Figure 1B)
The biggest challenges in the treatment of HPV-mediated cervical malignancy are associated with acquired local immune-suppression, and disruption of cellular homeostatic processes leading to impaired focal adhesion and breakdown of extracellular matrix, promoting cancer cell invasion, dissemination, and metastasis
Summary
Oncogenic human papillomavirus (HPV) infections are responsible for 5% of the global human cancer burden, resulting in over 634,000 new cancers annually, of which ∼90% are in women (Schiffman et al, 2016). E2 regulates cell differentiation and has been shown to interact with focal adhesion kinase PTK2B and FN1 (Muller and Demeret, 2012), two of the top scoring stemness pathway genes we identified to be associated with cervical cancer prognosis. Both of these proteins are involved in cellular adhesion, which suggests an early impact of the viral life cycle on stemness and on cohesion of the epithelium perhaps contributing to invasiveness. The association of these viral proteins with stemness-associated genes suggests a potential for a combined targeted therapy approach against cervical cancers
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