A critical role for IκB kinase α in the development of human and mouse squamous cell carcinomas

Abstract

IKK (I B kinase) ␣ is essential for embryonic skin development in mice. Mice deficient in IKK␣ display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKK␣ in human skin diseases remains largely unknown. To shed light on the role of IKK␣ in human skin diseases, we examined IKK␣ expression and Ikk␣ mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKK␣ expression in poorly differentiated human SCCs and identified Ikk␣ mutations in exon 15 of Ikk␣ in eight of nine human SCCs, implying that IKK␣ is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKK␣ in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKK␣ transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKK␣ in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.angiogenesis ͉ mitogenesis ͉ skin carcinogenesis ͉ differentiation ͉ tumor progression S quamous cell carcinomas (SCCs) can be very aggressive and metastatic. Previous studies have shown that Pten mutations are found frequently in human SCCs; however, these Pten mutations are not detected in all cases (1, 2). p53 mutations have also been identified in a large proportion of human SCCs (3); however, these p53 mutations can be latent in skin cells for years before the onset of this disease. Clearly, additional pivotal factors in the development of this human skin cancer remain to be identified.The I B kinase (IKK) complex consists of IKK␣, IKK␤, and IKK␥ (4-7), which phosphorylates I B␣ (S32͞S36) and I B␤ (S19͞S23) that are NF-B inhibitors. This phosphorylation event triggers the degradation of I B proteins via a 26S proteasomeubiquitination pathway, leading to NF-B translocation and activation. Previous findings have shown that IKK␣ is essential for embryonic skin development in mice (8-10). Mice lacking IKK␣ exhibit a strikingly hyperplastic epidermis, which lacks terminal differentiation, and they die of severely impaired skin soon after birth. The skin phenotypes of Ikk␣ Ϫ/Ϫ mice have not been observed in knockouts of any other NF-B family members. In contrast, mice overexpressing IKK␣ in the basal epidermis develop normally (11). The ectopic IKK␣ is able to induce terminal differentiation and to repress hyperplasia in the skin of Ikk␣ Ϫ/Ϫ mice, implying that IKK␣ plays a role in maintaining skin homeostasis (11).Although a role of IKK␣ in skin development in mice has been established, we still know little regarding the involvement of IKK␣ in human skin diseases. To shed light on the role of IKK␣ in human skin ...

Regulation of IKKβ by miR-199a affects NF-κB activity in ovarian cancer cells

“…By phosphorylating the inhibitor of NF-kB a (IkBa), activated IKKs promote the proteosome-mediated degradation of IkBa and nuclear translocation of NF-kB. Although IKKa is more important in cell differentiation, lymphoid organogenesis and the regulation of adaptive immunity (Hacker and Karin, 2006;Liu et al, 2006), IKKb is crucial for the production of proinflammatory cytokines that are related to cell survival and cell proliferation Hu et al, 2004). IKKb has been found highly active in many different types of cancer including breast cancer, pancreatic cancer, thyroidal C-cells carcinoma, melanoma and acute myeloid leukemia (Ludwig et al, 2001;Romieu-Mourez et al, 2001;Tamatani et al, 2001;Yang and Richmond, 2001;Baumgartner et al, 2002;Li et al, 2004).…”

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

“…Furthermore, TGF-␤ induces nuclear accumulation of IKK␣, and IKK␣ and SMAD3 coregulate the expression of several antiproliferative Myc antagonists (14). A tumor-suppressive role for IKK␣ in SCC was recently identified in a mouse model of chemically induced SCC and a small number of human samples (15). More recent evaluation of IKK␣ expression in SCC revealed its loss in about 30% of such cancers, especially in those that develop a highly invasive phenotype (16).…”

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

“…[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. [8][9][10]28,39 Furthermore, we showed that reducing EGFR repressed Stat3 activity, epidermis thickness, and inflammation in IKKa-deficient skin.…”

“…Several laboratories have demonstrated that IKKa expression was downregulated, or that its localization was altered in human squamous cell carcinomas of the skin, lungs, and head and neck, [16][17][18][19][20] highlighting the importance of IKKa in human malignancy development. We showed that induced IKKa deletion in keratinocytes causes epidermal hyperplasia and spontaneous skin tumors.…”

“…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. 16 …”