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Reduction in IB Kinase Expression Promotes the Development of Skin Papillomas and Carcinomas

Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas

Requests for reprints: Yinling Hu, Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, 1808 Park Road 1-C, Smithville, TX 78957. Phone: 512-237-9338; Fax: 512-237-4375; E-mail: yhu{at}mdanderson.org.

We reported recently a marked reduction in IB kinase (IKK) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikk mutations in human SCCs. In addition, overexpression of IKK in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKK expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikk hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikk^+/– mice developed 2 times more papillomas and 11 times more carcinomas than did Ikk^+/+ mice. The tumors were larger in Ikk^+/– than in Ikk^+/+ mice, but tumor latency was shorter in Ikk^+/– than in Ikk^+/+ mice. Some of the Ikk^+/– papillomas and most Ikk^+/– carcinomas lost the remaining Ikk wild-type allele. Somatic Ikk 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 Ikk^+/– than in Ikk^+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKK 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 IKK expression promotes the development of papillomas and carcinomas and that the integrity of the Ikk gene is required for suppressing skin carcinogenesis. [Cancer Res 2007;67(19):9158–68]