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Interferon regulatory factor 1 (IRF-1) transcription factor binds to DNA sequence elements found in the promoters of type I IFN and IFN-inducible genes. Transient up-regulation of the IRF-1 gene by virus and IFN treatment causes the consequent induction of many IFN-inducible genes involved in cell growth control and apoptosis. We reported recently that IFN-alpha and all-trans retinoic Acid (RA) inhibit the cell proliferation of squamous carcinoma cell line ME-180 by inducing apoptotic cell death. IRF-1 expression correlates with the IFN-alpha-induced apoptosis phenomenon and, surprisingly, with the RA-induced apoptosis phenomenon. To study how these two different ligands cross-talk in the regulation of cellular antitumor responses, the signalling pathways involved in IRF-1 induction were analyzed in RA and/or IFN-alpha-treated ME-180 cells. We provide evidence indicating that RA-induced IRF-1 gene expression is independent of the STAT-1 activation pathway, despite the presence of the IFN-gamma activated sequence element in the gene promoter, but involves nuclear factor-kappa B activation. Thus, here we first describe the activation of nuclear factor-kappa B by both IFN-alpha and RA in the ME-180 cell line. The induced IRF-1 protein is successively able to bind the IFN-stimulated responsive element in the promoter of the target gene 2',5'-oligoadenylate synthetase.

Simple Summary This review aims to collect recent studies on the complex relationship between the host innate response to oncogenic viruses (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and tumorigenic processes by focusing mainly on regulatory crosstalks between viral components and the type I IFN system. It is a picture of new mechanisms by which type I IFNs may be affected and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. Studies on cellular and viral miRNAs machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicle-mediated delivery are described. Abstract Oncogenic viruses favor the development of tumors in mammals by persistent infection and specific cellular pathways modifications by deregulating cell proliferation and inhibiting apoptosis. They counteract the cellular antiviral defense through viral proteins as well as specific cellular effectors involved in virus-induced tumorigenesis. Type I interferons (IFNs) are a family of cytokines critical not only for viral interference but also for their broad range of properties that go beyond the antiviral action. In fact, they can inhibit cell proliferation and modulate differentiation, apoptosis, and migration. However, their principal role is to regulate the development and activity of most effector cells of the innate and adaptive immune responses. Various are the mechanisms by which IFNs exert their effects on immune cells. They can act directly, through IFN receptor triggering, or indirectly by the induction of chemokines, the secretion of further cytokines, or by the stimulation of cells useful for the activation of particular immune cells. All the properties of IFNs are crucial in the host defense against viruses and bacteria, as well as in the immune surveillance against tumors. IFNs may be affected by and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. New data on cellular and viral microRNAs (miRNAs) machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicles-mediated delivery are reported. Recent research is reviewed on the tumorigenesis induced by specific viruses with RNA or DNA genome, belonging to different families (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and the IFN system involvement.

Anticancer drug-induced tumor suppression may involve mechanisms of protection against neoplastic transformation that are normally latent in mammalian cells and consist in a genetic program implemented during anti-tumoral defense. This defense program results in the self elimination of cells harboring potentially dangerous mutations by triggering cell death through apoptosis and/or autophagy or in the execution of a program that leads to a permanent growth arrest known as senescence. These responses are considered crucial tumor suppressive mechanisms and their study appears to be essential to develop therapeutical procedures based on the enhancement of the different responses. This review summarizes fundamental knowledge on the underlying mechanisms able to limit excessive or aberrant cellular proliferation and on the prognostic value of both apoptosis and senescence detection. In addition, interesting evidence showing that different drugs induce senescence or cell death depending on the genetic features of the tumor cells as well as on the integrity of the relative pathways is reported.