XPC protects against smoking- and carcinogen-induced lung adenocarcinoma
XPC protects against smoking- and carcinogen-induced lung adenocarcinoma
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DOI：
10.1093/carcin/bgz003
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发表时间：
2019-03-01
期刊：
影响因子：
4.7
通讯作者：
Sears, Catherine R.
中科院分区：
文献类型：
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作者：
Zhou, Huaxin;Saliba, Jacob;Sears, Catherine R.
香烟烟雾（CS）含有数百种致癌物质，是氧化和大体积DNA损伤的强力诱导剂，当修复不充分时，会导致DNA损伤反应的激活和可能的突变。DNA修复蛋白着色性干皮病C组（XPC）是引发CS诱导的DNA损伤中发挥重要作用，因为它的功能，在启动修复两个庞大的氧化DNA损伤。我们推测，XPC功能的丧失将通过氧化DNA损伤的修复受损而增加发生CS和致癌物诱导的肺癌的易感性。暴露于慢性CS的XPC缺陷小鼠（XPC-/-）发生了肺肿瘤，而其野生型同窝小鼠（XPC+/+）则没有。用CS-致癌物尿烷处理的XPC-/-小鼠发生了肺腺癌，代表肿瘤发展的进行性阶段，与XPC+/+小鼠相比，肺肿瘤数量增加了17倍。XPC杂合子小鼠（XPC+/-）表现出基因剂量效应，在乌拉坦治疗下发生中等数量的肺肿瘤。XPC-/-小鼠用致癌物3-甲基胆蒽处理，然后用增殖剂丁基羟基甲苯处理，导致肺腺癌发展增加2倍。最后，通过同时使用抗氧化剂N-乙酰半胱氨酸治疗，XPC-/-小鼠肺部的肿瘤数量减少了7倍。总之，这支持了一种机制，通过这种机制，减少XPC表达促进肺腺癌的发展，在响应CS-致癌物暴露，部分原因是受损的氧化DNA损伤修复。
Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS-and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/-mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/-mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/-mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair.