Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice

Guang Yang, David Curley, Marcus W Bosenberg, Hensin Tsao
Cancer Research 2007 June 15, 67 (12): 5649-57
Despite an extensive body of evidence linking UV radiation and melanoma tumorigenesis, a clear mechanistic understanding of this process is still lacking. Because heritable mutations in both INK4a and the nucleotide excision repair (NER) pathway predispose individuals to melanoma development, we set out to test the hypothesis that abrogation of NER, by deletion of the xeroderma pigmentosum C (Xpc) gene, will heighten melanoma photocarcinogenesis in an Ink4a-Arf-deficient background. Experimentally, we generated a strain of mice doubly deficient in Xpc and Ink4a-Arf and subjected wild-type, Xpc-/-Ink4a-Arf+/+, Xpc-/-Ink4a-Arf-/-, and Xpc+/+Ink4a-Arf-/- mice to a single neonatal (day P3) dose of UVB without additional chemical promotion. Indeed, there was a significant increase in the development of dermal spindle/epithelioid cell melanomas in Xpc-/-Ink4a-Arf-/- mice when compared with Xpc+/+Ink4a-Arf-/- mice (P = 0.005); wild-type and Xpc-/-Ink4a-Arf+/+ mice failed to develop tumors. These neoplasms bore a striking histologic resemblance to melanomas that arise in the Tyr-vHRAS/Ink4a-Arf-/- context and often expressed melanocyte differentiation marker Tyrp1, thus supporting their melanocytic origination. All strains, except wild-type mice, developed pigmented and non-pigmented epidermal-derived keratinocytic cysts, whereas Xpc+/+Ink4a-Arf-/- mice exhibited the greatest propensity for squamous cell carcinoma development. We then screened for NRas, HRas, Kras, and BRaf mutations in tumor tissue and detected a higher frequency of rare Kras(Q61) alterations in tumors from Xpc-/-Ink4a-Arf-/- mice compared with Xpc+/+Ink4a-Arf-/- mice (50% versus 7%, P = 0.033). Taken together, results from this novel UV-inducible melanoma model suggest that NER loss, in conjunction with Ink4a-Arf inactivation, can drive melanoma photocarcinogenesis possibly through signature Kras mutagenesis.

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