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

Abstract

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

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[7,9,10] Alternatively, IKKα suppresses carcinogenesis in the skin, lungs, esophagi, nasopharynges, and pancreas of humans and mice independently of canonical and noncanonical NF-kB pathways ( Figure 1B). [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] These findings highlight the medical importance of IKK/NF-kB in the pathogenesis of human diseases and malignancies.…”

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

“…It has been shown that deleting Stat3 in keratinocytes reduces chemical carcinogen and ultraviolet B-induced skin carcinogenesis, and that overexpressed Stat3 in the epidermis promotes skin carcinogenesis. [36][37][38] Conversely, deleting IKKa in keratinocytes causes spontaneous skin tumors, 15 reducing IKKa expression promotes chemical carcinogen and UVB-induced skin carcinogenesis, 24,27 and overexpressing IKKa in the epidermis inhibits the development of malignant skin tumors and metastases induced by chemical carcinogens. 16 It appears that Stat3 and IKKa have converse roles in skin carcinogenesis, although IKKa seems to have a more specific effect on embryonic skin development and keratinocyte differentiation than Stat3 does.…”

“…[21][22][23] We also found that IKKa expression levels were higher in skin papillomas, a benign form of skin tumors, compared with normal skin in C57BL6 mice. 24 Approximately, only 3-5% of the papillomas progress to malignant carcinomas, but the rest eventually regress in C57BL6 mice. 24 We found that C57BL6 Ikka þ /À mice developed twice as many papillomas as C57BL6 Ikka þ / þ mice.…”

“…24 Approximately, only 3-5% of the papillomas progress to malignant carcinomas, but the rest eventually regress in C57BL6 mice. 24 We found that C57BL6 Ikka þ /À mice developed twice as many papillomas as C57BL6 Ikka þ / þ mice. The levels of 12-O-tetradecanoylphorbol-13-acetate-induced IKKa were obviously lower in Ikka þ /À skin and papillomas than in Ikka þ / þ skin and papillomas, indicating that IKKa levels are important for preventing skin tumor development.…”

“…Total RNA was isolated from the epidermis or keratinocytes using TRI Reagent (Molecular Research Center). 24 cDNA was synthesized by a RETROscript kit (Ambion, Inc., Austin, TX, USA). PCR primers used included TNFa (5 0 -CACCACGCTCTTCTGTCTACTGAAC-3 0 and 5 0 -TGAGAT AGCAAATCGGCTGACG-3 0 ), IL-6 (5 0 -TCTGGGAAATCGTGGAAATGAG-3 0 and 5 0 -TCTCTGAAGGACTCTGGCTTTGTC-3 0 ), IL-1 (5 0 -CCAGGATGAGGACATGA GCACC-3 0 and 5 0 -TTCTCTGCAGACTCAAACTCCAC-3 0 ), and glyceraldehyde-3-phosphate dehydrogenase.…”