Human Papillomavirus and carcinogenesis: Novel mechanisms of cell communication involving extracellular vesicles

Abstract

A small group of mucosal Human Papillomaviruses are the causative agents of cervical cancer and are also associated with other types of cancers. Certain cutaneous Human Papillomaviruses seem to have a role as co-factors in the UV-induced carcinogenesis of the skin. The main mechanism of the tumorigenesis induced by Human Papillomaviruses is linked to the transforming activity of the viral E6 and E7 oncoproteins. However, other mechanisms, such as the gene expression control by specific microRNAs expression and deregulation of immune inflammatory mediators, may be important in the process of transformation. In this context, the release of Extracellular Vesicles with a specific cargo (microRNAs involved in tumorigenesis, mRNAs of viral oncoproteins, cytokines, chemokines) appears to play a key role.

Keywords: Extracellular vesicles; Inflammatory cytokines and chemokines; MicroRNAs; Mucosal and cutaneous HPVs; α-and β-HPVs.

Fig. 1

Biogenesis, secretion and cargo content of Extracellular Vesicles from HPV positive cells. EVs generated by outward budding and shedding from the plasma membrane (microvesicles or shed-microvesicles) or formed within multivesicular bodies (MVBs) as intraluminal vesicles (ILVs) released upon fusion of MVBs with the plasma membrane (exosomes), contain a specific set of bioactive molecules depending on both their biogenesis and HPV genotype (mucosal, upper panel or cutaneous, lower panel). In the boxes are reported specific microRNAs and mRNAs of viral oncoproteins as well as of inflammatory cytokines and chemokines delivered by EVs from mucosal HPV16 or cutaneous HPV38 E6 and E7 transduced cells. Arrows indicate the up- or down-regulation of mRNA expression with respect to EVs from control keratinocytes.