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- Title
Involvement of mtDNA Damage Elicited by Oxidative Stress in the Arsenical Skin Cancers.
- Authors
Lee, Chih-Hung; Wu, Shi-Bei; Hong, Chien-Hui; Chen, Gwo-Shin; Wei, Yau-Huei; Yu, Hsin-Su
- Abstract
Arsenic causes several human cancers. Arsenic-induced Bowen's disease (As-BD), the most common arsenical cancer, is characterized by increased proliferation, dysplasia, and individual cell apoptosis, all of which involve mitochondria. We reported that arsenic causes aberrant keratinocyte proliferation through mtTFA-mediated mitochondrial biogenesis in As-BD. Increasing mitochondrial biogenesis causes cells to undergo oxidative stress. However, how arsenic induces oxidative stress and causes mtDNA damage in arsenical cancers remains largely unknown. Using tissues from As-BD patients and arsenic-treated keratinocytes, we determined the oxidative stress, antioxidant enzymes, DNA-repair enzymes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in mtDNA by immunofluorescence, real-time PCR, and western blot. The results showed that oxidative stress was enhanced in both As-BD and arsenic-treated keratinocytes. Antioxidant enzymes including manganese-superoxide anion and copper/zinc-superoxide anion and DNA-repair enzymes were upregulated concomitantly in tissues and cells. In arsenic-treated keratinocytes, increased mitochondrial oxidative stress and the 8-OHdG level in mtDNA were attenuated by pretreatment with ascorbic acid, a potent antioxidant. Further, we found several somatic mutations in the ND4, ND5, and ND6 genes of mtDNA in lesional but not in perilesional skin from As-BD patients. Taken together, the results suggest that oxidative damage and mutations to mtDNA might be involved in the arsenical skin cancers in the context of mitochondrial biogenesis.
- Subjects
DNA damage; OXIDATIVE stress; SKIN cancer; DYSPLASIA; DNA repair; IMMUNOFLUORESCENCE; POLYMERASE chain reaction
- Publication
Journal of Investigative Dermatology, 2013, Vol 133, Issue 7, p1890
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1038/jid.2013.55