Journal Article

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1—NFκB—IL-6 signalling axis

Morgan, Ethan L., Macdonald, Andrew

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibodies / Apoptosis / Autocrine Communication / Autocrine signalling / Biology and Life Sciences / Cancer / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Carcinoma, Squamous Cell - virology / Cell cycle / Cell Line, Tumor / Cell proliferation / Cell survival / Cellular biology / Cervical cancer / Cervix / Coding / Conditioning / Cytokines / Drug resistance / E6 protein / Female / Gene expression / Guanosine triphosphatases / Hepatitis / Human papillomavirus / Human papillomavirus 16 / Human papillomavirus 18 / Humans / Infections / Inflammation / Interleukin 6 / Interleukin-6 - metabolism / Keratinocytes / Kinases / Medicine and Health Sciences / Molecular biology / Neoplasm Proteins - metabolism / NF-kappa B - metabolism / NF-κB protein / Paracrine signalling / Phosphorylation / Protein expression / Proteins / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Research and Analysis Methods / Signal Transduction / Stat3 protein / STAT3 Transcription Factor - metabolism / Transcription activation / Transcription factors / Transformation / Tumorigenesis / Uterine Cervical Neoplasms - metabolism / Uterine Cervical Neoplasms - pathology / Uterine Cervical Neoplasms - virology / Viruses / Wiring