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Inhibition of TGF-β and NOTCH Signaling by Cutaneous Papillomaviruses

Jordan M Meyers1,2, Miranda Grace2, Aayushi Uberoi3

  • 1Program in Virology, Harvard Medical School, Boston, MA, United States.

Frontiers in Microbiology
|March 24, 2018
PubMed

Insights

Mouse models of cutaneous human papillomavirus (HPV) infection reveal that MmuPV1 E6 protein inhibits key signaling pathways, driving wart and cancer development. This finding establishes a valuable system for studying HPV pathogenesis and carcinogenesis.

Area of Science:

  • Virology
  • Dermatology
  • Oncology

Background:

  • Cutaneous human papillomaviruses (HPVs) are associated with skin cancers, particularly in individuals with genetic disorders like epidermodysplasia verruciformis or those with long-term immunosuppression.
  • The E6 proteins of certain cutaneous HPVs, such as HPV5 and HPV8, are known to interfere with critical cellular signaling pathways, including TGF-β and NOTCH.
  • Cutaneous squamous cell carcinomas (cSCCs) represent a significant health concern, with HPV infections being a recognized risk factor in specific patient populations.

Purpose of the Study:

  • To investigate the role of Mus musculus papillomavirus 1 (MmuPV1) E6 protein in cutaneous carcinogenesis.
  • To determine if MmuPV1 E6 shares functional similarities with oncogenic HPV E6 proteins, specifically regarding TGF-β and NOTCH signaling inhibition.
  • To establish and validate the MmuPV1 mouse model as a system for studying cutaneous HPV pathogenesis and cancer development.

Main Methods:

  • Experimental infection of laboratory mice with MmuPV1.
  • Biochemical assays to assess MmuPV1 E6 binding to SMAD2/SMAD3 and MAML1 transcription factors.
  • Analysis of keratinocyte differentiation and proliferation in infected tissues.
  • Evaluation of wart and squamous cell carcinoma formation in MmuPV1-infected mice.

Main Results:

  • MmuPV1 E6 protein inhibits both TGF-β and NOTCH signaling pathways, similar to HPV8 E6.
  • Inhibition of these pathways by MmuPV1 E6 leads to delayed keratinocyte differentiation and sustained proliferation.
  • MmuPV1 E6 binding to MAML1 is essential for the development of warts and subsequent carcinogenesis in experimentally infected mice.
  • MmuPV1 infection in mice recapitulates key aspects of cutaneous HPV pathogenesis.

Conclusions:

  • The MmuPV1 E6 protein plays a critical role in promoting skin warts and squamous cell carcinomas by disrupting TGF-β and NOTCH signaling.
  • The MmuPV1 mouse model provides a robust platform for dissecting the molecular mechanisms underlying cutaneous HPV infection, pathogenesis, and carcinogenesis.
  • Understanding the function of MmuPV1 E6 offers insights into the broader field of HPV-driven skin cancer development.
Keywords:
epidermodysplasia verruciformishit-and-run carcinogenesiskeratinocyte differentiationsquamous cell carcinomaviral oncogenesis

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