How Does HPV Virus Lead To Skin Cancer?

MedicalResearch.com Interview with:
Prof. Dr. med. Sigrun Smola
Institute of Virology, Saarland University
Homburg/Saar, Germany

MedicalResearch.com: 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.


MedicalResearch.com: 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.

MedicalResearch.com: 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.

MedicalResearch.com: 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.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

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.

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