XPC protects against smoking- and carcinogen-induced lung adenocarcinoma

Huaxin Zhou, Jacob Saliba, George Sandusky, Catherine Sears

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalCarcinogenesis
Volume40
Issue number3
DOIs
StatePublished - May 14 2019

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Xeroderma Pigmentosum
Carcinogens
Smoking
Smoke
Tobacco Products
DNA Damage
Lung
Urethane
Neoplasms
DNA Repair
Adenocarcinoma of lung
Butylated Hydroxytoluene
Methylcholanthrene
Acetylcysteine
Lung Neoplasms
Antioxidants

ASJC Scopus subject areas

  • Cancer Research

Cite this

XPC protects against smoking- and carcinogen-induced lung adenocarcinoma. / Zhou, Huaxin; Saliba, Jacob; Sandusky, George; Sears, Catherine.

In: Carcinogenesis, Vol. 40, No. 3, 14.05.2019, p. 403-411.

Research output: Contribution to journalArticle

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