Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice.
Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice.
复制标题
色素性干皮病 C (Xpc) 的缺失会增强 Ink4a-Arf 缺陷小鼠的黑色素瘤光致癌作用。
DOI：
10.1158/0008-5472.can-06-3806
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发表时间：
2007
期刊：
影响因子：
11.2
通讯作者：
Tsao,Hensin
中科院分区：
文献类型：
--
作者：
Yang,Guang;Curley,David;Bosenberg,MarcusW;Tsao,Hensin
尽管有大量的证据表明紫外线辐射和黑色素瘤的发生有关，但对这一过程仍缺乏明确的机制理解。由于INK 4a和核苷酸切除修复（NER）途径的遗传突变使个体易患黑色素瘤，我们着手验证以下假设：通过缺失色素性外膜蛋白C（Xpc）基因，废除NER将在Ink 4a-Arf缺陷背景下增强黑色素瘤光致癌作用。在实验中，我们产生了一种XpcandInk 4a-Arf双重缺陷的小鼠品系，并使野生型、Xpc−/− Ink 4a-Arf +/+、Xpc−/− Ink 4a-Arf −/−和Xpc +/+ Ink 4a-Arf −/−小鼠接受单次新生（P3天）剂量的UVB照射，而没有额外的化学促进。事实上，与Xpc +/+ Ink 4a-Arf −/−小鼠相比，Xpc −/− Ink 4a-Arf −/−小鼠中皮肤梭形/上皮样细胞黑色素瘤的发生显著增加（P= 0.005）;野生型和Xpc −/− Ink 4a-Arf +/+小鼠没有发生肿瘤。这些肿瘤在组织学上与Tyr-vHRAS/Ink 4a-Arf −/−背景下产生的黑色素瘤有惊人的相似性，并且经常表达黑素细胞分化标记物Tyrp 1，从而支持它们的黑素细胞起源。除野生型小鼠外，所有品系均出现色素性和非色素性表皮源性角化细胞囊肿，而Xpc +/+ Ink 4a-Arf −/−小鼠表现出发生鳞状细胞癌的最大倾向。然后，我们在肿瘤组织中筛选NRas、HRas、Kras和BRaf突变，并检测到Xpc −/− Ink 4a-Arf −/−小鼠肿瘤中罕见KrasQ 61改变的频率高于Xpc +/+ Ink 4a-Arf −/−小鼠（50%对7%，P = 0.033）。综上所述，来自这种新型UV诱导的黑色素瘤模型的结果表明，NER损失与Ink 4a-Arf活化结合，可以驱动黑色素瘤光致癌可能通过签名Krasmutagenesis。[Cancer Res 2007;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 bothINK4aand 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 thexeroderma pigmentosum C(Xpc) gene, will heighten melanoma photocarcinogenesis in anInk4a-Arf–deficient background. Experimentally, we generated a strain of mice doubly deficient inXpcandInk4a-Arfand subjected wild-type,Xpc−/−Ink4a-Arf+/+,Xpc−/−Ink4a-Arf−/−, andXpc+/+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 inXpc−/−Ink4a-Arf−/−mice when compared withXpc+/+Ink4a-Arf−/−mice (P= 0.005); wild-type andXpc−/−Ink4a-Arf+/+mice failed to develop tumors. These neoplasms bore a striking histologic resemblance to melanomas that arise in theTyr-vHRAS/Ink4a-Arf−/−context and often expressed melanocyte differentiation markerTyrp1, thus supporting their melanocytic origination. All strains, except wild-type mice, developed pigmented and non-pigmented epidermal-derived keratinocytic cysts, whereasXpc+/+Ink4a-Arf−/−mice exhibited the greatest propensity for squamous cell carcinoma development. We then screened forNRas, HRas, Kras, andBRafmutations in tumor tissue and detected a higher frequency of rareKrasQ61alterations in tumors fromXpc−/−Ink4a-Arf−/−mice compared withXpc+/+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 withInk4a-Arfinactivation, can drive melanoma photocarcinogenesis possibly through signatureKrasmutagenesis. [Cancer Res 2007;67(12):5649–57]