Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas.

Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Research Abstract Details 

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Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Abstract Text:

Eunmi Park,Feng Zhu,Bigang Liu,Xiaojun Xia,Jianjun Shen,Tracie Bustos,Susan M Fischer,Yinling Hu,

We reported recently a marked reduction in IkappaB kinase alpha (IKKalpha) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkalpha mutations in human SCCs. In addition, overexpression of IKKalpha in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKalpha expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkalpha hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkalpha+/- mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkalpha+/+ mice. The tumors were larger in Ikkalpha+/- than in Ikkalpha+/+ mice, but tumor latency was shorter in Ikkalpha+/- than in Ikkalpha+/+ mice. Some of the Ikkalpha+/- papillomas and most Ikkalpha+/- carcinomas lost the remaining Ikkalpha wild-type allele. Somatic Ikkalpha mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikkalpha+/- than in Ikkalpha+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKalpha expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive extracellular signal-regulated kinase and IKK kinase activities were observed in carcinomas compared with those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKalpha expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkalpha gene is required for suppressing skin carcinogenesis.

Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Publishing Authors By Initials

E Park,F Zhu,B Liu,X Xia,J Shen,T Bustos,SM Fischer,Y Hu,

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Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 67

Page Numbers: 9158-68

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 1

MONTH: Oct

YEAR: 2007

Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas.

AFFILIATION: Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: ES07784

ACRONYM: ES

MEDLINETA: Cancer Res

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