STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle

Morgan, Ethan L.; Wasson, Christopher W.; Hanson, Lucy; Kealy, David; Pentland, Ieisha; McGuire, Victoria A.; Scarpini, Cinzia; Coleman, Nicholas; Arthur, J. Simon C.; Parish, Joanna L; Roberts, Sally; Macdonald, Andrew

doi:10.1371/journal.ppat.1006975

Cited by 71 publications

(116 citation statements)

References 88 publications

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“…To confirm if IL-6 expression was necessary for E6-mediated STAT3 phosphorylation, HPV18 E6 was expressed in C33A cells which were then treated with neutralising antibodies against either IL-6 or the gp130 co-receptor. As we have previously shown, the expression of HPV E6 induced STAT3 phosphorylation at both Y705 and S727 residues in C33A cells [19]. Treatment of E6 expressing cells with neutralising antibodies against IL-6 or gp130 led to the loss of STAT3 phosphorylation (Fig 5H).…”

Section: Resultssupporting

confidence: 71%

“…The increased STAT3 phosphorylation observed in HPV containing keratinocytes is dependent on the E6 oncoprotein [19]. Additionally, HPV16 E6 has been previously demonstrated to induce IL-6 secretion in non-small cell lung cancer (NSCLC) cells [24].…”

Section: Resultsmentioning

confidence: 99%

“…Several oncogenic viruses activate STAT3 to drive cellular proliferation, viral replication and tumourigenesis [18]. Using a primary cell culture model, we have previously shown that E6 activates the STAT3 signalling pathway in primary keratinocytes during the HPV lifecycle [19]. Additionally, we showed that STAT3 activation and expression correlates with cervical disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Oncogenic viruses can activate STAT3 to drive cellular proliferation, necessary for viral replication and tumourigenesis [18]. Using a primary keratinocyte cell culture model, we previously demonstrated that E6 activates STAT3 signalling during the productive HPV lifecycle [19]. STAT3 activation was essential for the hyperplasia observed in HPV-containing keratinocyte raft culture models.…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 activation was essential for the hyperplasia observed in HPV-containing keratinocyte raft culture models. Increased STAT3 protein expression and phosphorylation also correlated with cervical disease progression in a panel of cytology samples [19]. Although we identified that Janus kinase 2 (JAK2) and MAP kinases were necessary for STAT3 phosphorylation in HPV-containing primary keratinocytes, our understanding of the mechanisms by which E6 mediates this process remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

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Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

Morgan

Macdonald

2018

Preprint

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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 remain poorly 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 non-conventional activation of the transcription factor NF?B, involving the protein kinase Akt, 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. 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.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

Morgan

Macdonald

2018

Preprint

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The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

Jiang

Qian

et al. 2020

Molecular Oncology

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Cervical cancer is induced by persistent infections with high‐risk human papillomaviruses (HPVs), which produce the early protein 6 of HPVs (E6)/E7 protein that is involved in cell transformation by interacting with several oncoproteins or tumor suppressors. However, the role of noncoding RNA in mediating the pathogenesis of cervical cancer remains unclear. Here, we report that the novel signal transducer and activator of transcription 3 (STAT3)‐microRNA‐223‐3p (miR‐223)‐TGFBR3/HMGCS1 axis regulated by the E6 protein controls cervical carcinogenesis. miR‐223 was highly expressed in cervical tumor tissues, whereas TGFBR3 or HMGCS1 was significantly downregulated. miR‐223 targeted the 3′‐UTRs of TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage‐independent growth and cervical squamous cell carcinoma (CSCC) tumor growth in vitro and in vivo. The increased expression of miR‐223 was mediated by the transcription factor STAT3, whose activity was enhanced by E6 in the context of interleukin (IL)‐6 stimulation. In addition, exosomal miR‐223 derived from CSCC cells induced IL‐6 secretion by monocyte/macrophage in a coculture system in vitro, and IL‐6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR‐223 inhibitor effectively suppressed tumor growth in cell line‐derived xenograft model, suggesting that miR‐223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3‐miR‐223‐HMGCS1/TGFBR3 axis functions as a key signaling pathway in cervical cancer progression and provides a new therapeutic target.

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3D Oral and Cervical Tissue Models for Studying Papillomavirus Host‐Pathogen Interactions

et al. 2020

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Human papillomavirus (HPV) infection occurs in differentiating epithelial tissues. Cancers caused by high-risk types (e.g., HPV16 and HPV18) typically occur at oropharyngeal and anogenital anatomical sites. The HPV life cycle is differentiation-dependent, requiring tissue culture methodology that is able to recapitulate the three-dimensional (3D) stratified epithelium. Here we report two distinct and complementary methods for growing differentiating epithelial tissues that mimic many critical morphological and biochemical aspects of in vivo tissue. The first approach involves growing primary human epithelial cells on top of a dermal equivalent consisting of collagen fibers and living fibroblast cells. When these cells are grown at the liquid-air interface, differentiation occurs and allows for epithelial stratification. The second approach uses a rotating wall vessel bioreactor. The low-fluid-shear microgravity environment inside the bioreactor allows the cells to use collagen-coated microbeads as a growth scaffold and self-assemble into 3D cellular aggregates. These approaches are applied to epithelial cells derived from HPV-positive and HPV-negative oral and cervical tissues. The second part of the article introduces potential downstream applications for these 3D tissue models. We describe methods that will allow readers to start successfully culturing 3D tissues from oral and cervical cells. These tissues have been used for microscopic visualization, scanning electron microscopy, and large omics-based studies to gain insights into epithelial biology, the HPV life cycle, and host-pathogen interactions.

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STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle

Cited by 71 publications

References 88 publications

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

3D Oral and Cervical Tissue Models for Studying Papillomavirus Host‐Pathogen Interactions

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