How Does HPV Virus Lead To Skin Cancer? Interview with:
Prof. Dr. med. Sigrun Smola
Institute of Virology, Saarland University
Homburg/Saar, Germany What is the background for this study?

Response: Non-melanoma skin cancer (NMSC), the most common cancer in humans, is caused by UV-irradiation. The potential co-factor role of cutaneous genus beta-human papillomaviruses (beta-HPV) in skin carcinogenesis, particularly in immunosuppressed patients, has become a major field of interest. However, the underlying mechanisms were unclear.

The skin has natural mechanisms providing protection against UV-induced damage. One important factor suppressing UV-induced skin carcinogenesis is the transcription factor C/EBPα belonging to the CCAAT/enhancer binding protein family. C/EBPα can induce cellular differentiation and is regarded as a tumor suppressor in various tissues. When C/EBPα expression is blocked in these tissues, tumorigenesis is enhanced.

Another important factor is the microRNA-203. It has been shown to control “stemness” in normal skin by suppressing a factor called p63. In many tumors miR-203 expression is shut off releasing this “brake”.

In our study we demonstrate that cutaneous beta-HPV interferes with both protective factors providing an explanation how cutaneous beta-HPV enhances the susceptibility to UV-induced carcinogenesis. Moreover, we provide evidence that these viruses regulate miR-203 via C/EBPα.

We have investigated this mechanism in Epidermodysplasia verruciformis (EV) patients that serve as a human model disease for studying the biology of genus beta-HPVs. They are highly susceptible to persistent genus beta-HPV infection, such as HPV8, and have an increased risk to develop non-melanoma skin cancer at sun-exposed sites. What are the main findings?

• We demonstrate that the tumor suppressor C/EBPα is almost absent in HPV8 infected skin lesions of EV-patients. Our data provide evidence that the HPV8 encoded E6 oncoprotein down-regulates C/EBPα in a p300-dependent manner.
• Notably, our study has also identified the “stemness-repressing” miR-203 as a novel direct target of C/EBPα. miR-203 is known to control p63, a key regulator of epidermal proliferation and differentiation.
• Accordingly, we found that miR-203 expression patterns in human skin parallels C/EBPα expression. HPV8-positive EV-lesions are almost devoid of miR-203, while p63-expressing cells are largely amplified.
• We demonstrate that this novel p300/C/EBPα/miR-203/p63-dependent pathway plays a substantial role in HPV8 E6-induced keratinocyte proliferation and suppression of differentiation.
Our study demonstrates that HPV8 disturbs epidermal homeostasis and explains the underlying mechanism. Importantly, our data provide evidence for a novel p300/C/EBPα/miR-203-dependent pathway that links HPV8 infection to the expansion of p63-positive progenitor cells in the epidermis of EV-patients. This may drive HPV-induced pathogenesis in these patients and may pave the way for skin carcinogenesis. What should clinicians and patients take away from your report?

• Our findings provide an explanation how certain cutaneous HPV can enhance the susceptibility to UV-induced skin carcinogenesis.
• HPV8 interferes with a pathway suppressing UV-induced carcinogenesis in skin.
• This novel mechanism involves a previously unknown C/EBPα-miRNA-203 axis that may also play a role in other cancers. What recommendations do you have for future research as a result of this study?

Response: It will be interesting to study the impact of this novel C/EBPα-miR-203 axis for carcinogenesis in other tissues.
Our study opens up a new field for research on drugs that can reconstitute this pathway. Thank you for your contribution to the community.


Identification of C/EBPα as a novel target of the HPV8 E6 protein regulating miR-203 in human keratinocytes

Anna M. Marthaler, et al

Published: June 22, 2017

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

Last Updated on June 22, 2017 by Marie Benz MD FAAD