PTEN Downregulation Impairs UVB-Induced DNA Damage Repair
Suppresses xeroderma pigmentosum C-dependent genomic excision repair in mice
WEDNESDAY, July 27 (HealthDay News) -- Downregulation of the tumor suppressor PTEN suppresses xeroderma pigmentosum C (XPC)-dependent genomic nucleotide excision repair (GG-NER), according to an experimental study published online July 19 in Cancer Research.
Mei Ming, Ph.D., from the University of Chicago, and colleagues investigated whether attenuating PTEN in epidermal keratinocytes is a predisposing factor for ultraviolet B (UVB)-induced skin carcinogenesis in mice. A total of 15 shaved mice were exposed to UVB radiation, and PTEN protein levels were determined by immunohistochemistry. UVB-induced tumor formation was compared between mice with normal PTEN and mice with PTEN hemizygosity. PTEN protein levels of keratinocytes in interfollicular epidermis were evaluated in 69 human samples to understand the role of PTEN in human skin cancer.
The investigators found that PTEN levels were reduced in skin papilloma and squamous cell carcinoma (SCC) as compared with skin lacking these lesions. PTEN levels were suppressed in human premalignant actinic keratosis and malignant SCCs. PTEN downregulation impaired global GG-NER capacity, increased the activation of Chk1 DNA damage pathway in an AKT-independent manner, and prolonged UVB-induced growth arrest, but did not respond in the same way to ionizing radiation. Expression of the key GG-NER protein XPC was also suppressed on loss of PTEN through AKT/p38 signaling axis. XPC levels reconstituted in PTEN-inhibited cells restored GG-NER capacity.
"PTEN downregulation is a predisposing factor for UVB-induced skin carcinogenesis in vivo and negatively regulates UVB-induced DNA damage repair through limiting XPC expression," the authors write.