Inflammatory microenvironment and human papillomavirus-induced carcinogenesis

Introduction: 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. Methods: To study the tumorigenic role of inflammatory mediators in HPV+ cells, it has been analyzed by real time RT-PCR the expression of selected inflammatory cytokines, chemokines and related molecules in human foreskin keratinocytes transduced by E6 and E7 from mucosal (HPV-16) or cutaneous (HPV-38) genotypes comparing them to primary Human Foreskin Keratinocytes (HFK). It has been evaluated the contribution of the single E6 or E7 from HPV-16 by using human foreskin keratinocytes transduced by E6 or E7. On the other hand the specific involvement of the viral proteins has been analyzed by silencing experiments with E6/E7 siRNA. Results: IL-1a and IL-1b mRNAs are downregulated in K16 and K38 cells. Silencing experiments have been confirmed the specificity of the effect. IL-6 mRNA appeared to be slightly upregulated in K16, by the synergic action of E6 and E7 oncoproteins, and downregulated in K38. IL-1R1 mRNA level is comparable in all cell lines. The expression of CCL2/MCP-1, CCL20/MIP-3a and CCL27/CTACK is downregulated both in K16 and K38 cells but CCL2/MCP-1, CCL20/MIP-3a seem to be restored by E6 and E7 from HPV-16 silencing. Our results suggest that the expression of HPV oncoproteins allows the modification of the tumor microenvironment through the synthesis and release of specific pro-inflammatory cytokines and chemokines leading to the interference with the leucocytes trafficking and/or a better tumor growth and infiltration. Conclusion: The role of inflammatory microenvironment in the HPV-induced carcinogenesis is addressed, with a specific focus on the involvement of the immune molecules and microRNAs as well as their delivery through the microvesicle cargo possibly correlated to the single transforming or untransforming HPV genotype.