Human Papillomavirus E6 and E7 oncoproteins affect the cell microenvironment by classical secretion and extracellular vesicles delivery of inflammatory mediators.

ABSTRACT

The connection between chronic inflammation and risk of cancer has been supported by several studies. The development of cancer might be a process driven by the presence of a specific combination of inflammatory mediators, including cytokines, chemokines and enzymes, in the tumor microenvironment. Virus-induced tumors, like HPV-induced Squamous Cell Carcinomas, represent a paradigmatic example of the interplay between inflammation, as integral part of the innate antiviral response, and malignant transformation. Here, the role of inflammatory microenvironment in the HPV-induced carcinogenesis is addressed, with a specific focus on the involvement of the immune molecules as well as their delivery through the microvesicle cargo possibly correlated to the different HPV genotype. The expression of the inflammatory mediators in HPV positive cells has been analyzed in primary human foreskin keratinocytes and keratinocytes transduced by E6 and E7 from mucosal HPV-16 or cutaneous HPV-38 genotypes. HPV E6 and E7 proteins can modulate the expression of immune mediators in HPV-infected cells and can affect the levels of immune molecules, mainly chemokines, in the extracellular milieu. HPV-16 E6 and E7 oncoproteins have been silenced to confirm the specificity of the modulation of the inflammatory microenvironment. Our results suggest that the expression of HPV oncoproteins allows the modification of the tumor milieu through the synthesis and release of specific pro-inflammatory cytokines and chemokines, affecting the efficacy of the immune response. The microenvironment can also be conditioned by an altered mRNA cargo delivered by extracellular vesicles, thereby efficiently affecting the surrounding cells with possible implication for tumorigenesis and tumor diagnosis.