Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

Abstract

Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

Keywords: HPV; JAK; STAT; cancer; cytokine signalling; interferon signalling.

Figure 1

Human papillomavirus (HPV) 16 genome organisation and viral life cycle. (A) Organisation of the HPV16 genome, showing the relative position of the early viral genes (E1, E2, E4, E5, E6, E7 and E8^E2), the late viral genes (L1 and L2) and the upstream regulatory region (URR). The position of the early and late promoter regions is shown. (B) Schematic of epithelial architecture and the stages of the viral life cycle, highlighting viral genome expression profile. Details are explained in the text. Red nuclei indicate mitotically active cells. The presence of episomal HPV genomes maintains cells in a mitotically active state upon migration into the spinous layers of the epithelium, where viral amplification and late gene expression occurs. HPV virions are then released in leaky squames that are sloughed off the top layers of the epithelia. Figure created using BioRENDER.com.

Figure 2

Schematic of Signal Transducer and Activator of Transcription (STAT) protein domain architecture and the biological defects and phenotypes observed in STAT family member knockout (KO) mice. IL, interleukin; IFN, interferon; EPO, erythropoietin; GM-CSF, granulocyte macrophage colony stimulating factor; N, N-terminal domain; CC, coiled coil domain; DBD, DNA-binding domain; LD, linker domain; SH2, Src Homology 2; TA, Transactivation domain [90,91,92,93,94,95,96,97]. Figure created using BioRENDER.com.

Figure 3

Schematic of Janus kinase (JAK) protein domain architecture and the mechanism of JAK activation. (A) JAK domain architecture and the biological defects and phenotypes observed in JAK family member knockout (KO) mice. gp130, glycoprotein 130; IL-6, interleukin 6; IL-6R, IL-6 receptor; FERM, 4.1 protein, Ezrin, Radixin, Moesin; SH2, Src Homology 2; JH2, JAK homology domain 2; JH1, JAK homology domain 1. (B) The mechanism of JAK activation. Details are discussed in the text. IL, interleukin; IFN, interferon; EPO, erythropoietin; GM-CSF, granulocyte macrophage colony stimulating factor; SCID, Severe Combined Immunodeficiency [98,99,100,101]. Figure created using BioRENDER.com.

Figure 4

Overview of the JAK/STAT signalling pathway. Upon extracellular ligand binding to their cognate receptors, auto- and/or trans-phosphorylation of JAKs and receptor tyrosine residues occurs, acting as docking sites for STAT proteins. JAK activation leads to the phosphorylation, dimerisation and activation of STAT proteins. Dimerised STATs then translocate into the nucleus and regulate gene transcription by binding to ISRE or GAS elements. Detailed descriptions are outlined in the text. IL, interleukin; IFN, interferon; IFNAR, IFN-α receptor; IFNGR, INF-γ receptor; IFNLR, IFN-λ receptor; EGF, epidermal growth factor; EGFR, EGF receptor; GM-CSF, granulocyte macrophage colony stimulating factor; S1P, sphingosine-1-phosphate; S1PR1, sphingosine-1-phosphate receptor 1; SFKs, Src family kinases; IRF9, interferon regulatory factor 9; ISGF3, interferon stimulated gene factor 3; ISRE, interferon stimulated response element; GAS, gamma interferon activation site. Figure created using BioRENDER.com.

Figure 5

Modulation of interferon induced STAT1/2 signalling by HPV. Diagram of interferon signalling via STAT1/2; the interaction of the HPV proteins is highlighted. (a) HPV E6 interacts with TYK2, inhibiting IFN signalling. (b) HPV E6 and E7 transcriptionally repress STAT1 expression. (c) HPV E7 bind to IRF9, blocking the formation of ISGF3. (d) HPV E5 and E6 transcriptionally repress IFNκ expression, inhibiting downstream STAT1 signalling. The effect of viral infection and the HPV genome is not included in the figure but is discussed in the text. IFN, interferon; IFNAR, IFN-α receptor; IFNGR, INF-γ receptor; IFNLR, IFN-λ receptor; IRF9, interferon regulatory factor 9; ISGF3, interferon stimulated gene factor 3; ISRE, interferon stimulated response element; GAS, gamma interferon activation site. Figure created using BioRENDER.com.

Figure 6

HPV modulation of the STAT3 signalling pathway. Diagram of STAT3 signalling. The interaction of the HPV proteins is highlighted. (a) HPV E6 induces IL-6 expression via a Rac1/NFκB signalling axis, resulting in autocrine/paracrine STAT3 signalling. (b) HPV E6 induces the degradation of p53, resulting in the reduction of the STAT3-targetting miRNAs miR-125a and Let-7a. (c) HPV E5, E6 and E7 can all induce EGFR signalling, which leads to downstream STAT3 activation. The effect of viral infection and the HPV genome is not included in the figure but is discussed in the text. IL, interleukin; EGF, epidermal growth factor; EGFR, EGF receptor; GM-CSF, granulocyte macrophage colony stimulating factor; SFKs, Src family kinases; GAS, gamma interferon activation site; E6-AP, E6-associated protein; NEMO, NFκB essential modifier; IκBα, inhibitor of NFκBα; IKK, IκB kinase. Figure created using BioRENDER.com.

Figure 7

HPV modulation of the STAT5 signalling pathway. Diagram of STAT5 signalling. The interaction of the HPV proteins is highlighted. (a) HPV E7 activates STAT5 via the inhibition of FBWX7-induced KLF13 degradation. (b) HPV E6 induces STAT5 activation via the E6-AP mediated degradation of PDZRN3. (c) HPV E5, E6 and E7 can all induce EGFR signalling, which leads to downstream STAT5 activation. The effect of viral infection and the HPV genome is not included in the figure but is discussed in the text. IL, interleukin; EGF, epidermal growth factor; EGFR, EGF receptor; EPO, erythropoietin; SFKs, Src family kinases; KLF13, Krϋppel-like factor 13; FBXW7, F-box/WD repeat-containing protein 7; E6-AP, E6-associated protein; GAS, gamma interferon activation site. Figure created using BioRENDER.com.