Abstract
Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Although the fundamental link between HPV infection and oncogenesis is established, the specific mechanisms of virus-mediated transformation are not fully understood. We previously demonstrated that the HPV encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 in primary human keratinocytes; however, the molecular basis for STAT3 activation in cervical cancer remains unclear. Here, we show that STAT3 phosphorylation in HPV positive cervical cancer cells is mediated primarily via autocrine activation by the pro-inflammatory cytokine Interleukin 6 (IL-6). Antibody-mediated blockade of IL-6 signalling in HPV positive cells inhibits STAT3 phosphorylation, whereas both recombinant IL-6 and conditioned media from HPV positive cells leads to increased STAT3 phosphorylation within HPV negative cervical cancer cells. Interestingly, we demonstrate that activation of the transcription factor NFκB, involving the small GTPase Rac1, is required for IL-6 production and subsequent STAT3 activation. Our data provides new insights into the molecular re-wiring of cancer cells by HPV E6. We reveal that activation of an IL-6 signalling axis drives the autocrine and paracrine phosphorylation of STAT3 within HPV positive cervical cancers cells and that activation of this pathway is essential for cervical cancer cell proliferation and survival. Greater understanding of this pathway provides a potential opportunity for the use of existing clinically approved drugs for the treatment of HPV-mediated cervical cancer.
Highlights
Human papillomaviruses (HPV) are a leading cause of squamous cell carcinomas of the anogenital and oropharyngeal epithelium [1]
We identified that Janus kinase 2 (JAK2) and MAP kinases were necessary for STAT3 phosphorylation in HPV negative (HPV-)containing primary keratinocytes, our understanding of the mechanisms by which E6 mediates this process remains incomplete
STAT3 protein expression and phosphorylation is increased in HPV positive compared with HPV negative cervical cancer cells
Summary
Human papillomaviruses (HPV) are a leading cause of squamous cell carcinomas of the anogenital and oropharyngeal epithelium [1]. HR-HPVs encode three oncogenic proteins: E5, E6 and E7, which interact with a multitude of host factors to manipulate signalling pathways necessary for cellular transformation. Whilst the role of the membrane protein E5 in cellular transformation is relatively poorly understood, it has been shown to activate EGFR signalling [3], which is necessary for transformation in vivo [4]. HR-E6 proteins bind and regulate a selection of PSD95/DLG/ZO-1 (PDZ) domain containing proteins [14,15]. In addition to these classical interactions, emerging evidence shows targeting of additional signalling pathways, including the Wnt and Hippo pathways, contributes to transformation by the HPV oncoproteins [16,17,18]
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