XPC protects against smoking- and carcinogen-induced lung adenocarcinoma

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 impor...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2019-05, Vol.40 (3), p.403-411
Main Authors: Zhou, Huaxin, Saliba, Jacob, Sandusky, George E, Sears, Catherine R
Format: Article
Language:English
Subjects:
Adenocarcinoma - chemically induced
Adenocarcinoma - metabolism
Adenocarcinoma - prevention & control
Animals
Biology, Genetics and Epigenetics
Carcinogens - toxicity
Cigarette Smoking - adverse effects
DNA Damage
Female
Humans
Lung Neoplasms - chemically induced
Lung Neoplasms - metabolism
Lung Neoplasms - prevention & control
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Urethane - toxicity
Xeroderma Pigmentosum - metabolism
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Summary: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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgz003