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Carcinogenesis Advance Access published online on May 27, 2004

Carcinogenesis, doi:10.1093/carcin/bgh195
© 2004 by Oxford University Press
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Received January 19, 2004
Revised May 10, 2004
Accepted May 16, 2004

CARCINOGENESIS

Increased skin carcinogenesis in a keratinocyte directed thioredoxin-1 transgenic mouse

Debbie Mustacich 1, Amary Wagner 1, Ryan Williams 1, Warner Bair 1, Loreta Barbacheck 1, Steven Stratton 1, Achyut K. Bhattacharyya 2, Garth Powis 1*

1 Arizona Cancer Center, University of Arizona, Tucson, Arizona, 85724, USA
2 Department of Pathology, University of Arizona, Tucson, Arizona, 85724, USA

* To whom correspondence should be addressed. E-mail: gpowis{at}azcc.arizona.edu.


   Abstract

Thioredoxin-1 is a low molecular weight redox protein that protects cells against oxidant damage. Thioredoxin-1 levels are increased in the epidermal layer of sun damaged human skin. Thioredoxin-1 levels are also increased in several human primary tumors where its expression is associated with increased tumor cell proliferation, decreased apoptosis and aggressive tumor growth . We have investigated whether increased thioredoxin-1 levels in skin can lead to increased tumor formation using transgenic mice with mouse thioredoxin-1 expressed in keratinocytes under the control of the keratinocyte-14 (K14) promoter. Thioredoxin-1 protein expression was increased 2 fold in the keratinocyte layer of the transgenic mice. The skin was macroscopically and histologically normal but in the two stage model of carcinogenesis using topical dimethylbenzanthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13- acetate (TPA) as a promoting agent, there was a 6 fold increase in the number of papillomas per mouse and a 3 fold increase in papilloma size in the K14 thioredoxin-1 transgenic mice compared to non-transgenic littermates. Thus, increased thioredoxin-1 in keratinocytes acts as an enhancer of carcinogenesis in the DMBA/TPA two stage model of skin carcinogenesis in mice.

Key Words: thioredoxin-1, skin, keratinocytes, carcinogenesis


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