Moreno-Maldonado R, Ramirez A, Navarro M, Fernandez-Acenero MJ, Villanueva C, Page A et al.. IKKalpha enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas. Cell Cycle 7: 2021-2029

Department of Epithelial Biology, CIEMAT, Madrid, Spain.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 08/2008; 7(13):2021-9. DOI: 10.4161/cc.7.13.6147
Source: PubMed


Squamous cell carcinomas (SCCs) of the skin display different clinical features according to their epithelial differentiation grade and histological variant. Understanding the causes of these divergences might increase the curability of SCCs. Therefore, it is important to study the mechanisms of differentiation in keratinocytes. IKK (IkappaB kinase) alpha is an important protein for epidermal morphogenesis, although the pathways through which it exerts its function are unknown and controversy exists about its role in cancer development. We show that enhanced IKKalpha expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKKalpha in mouse tumorigenic epidermal cells leads to changes in the differentiation pattern of the resulting SCCs, originating a distinct histological variant that resembles the human acantholytic SCC (ASCC) variant. Although human ASCCs have an aggressive clinical course and high risk of metastasis, nothing is known about their etiology. We show that human ASCCs, as observed in the counterpart IKKalpha murine tumors, express high levels of both IKKalpha and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKKalpha and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKalpha is responsible for the development of this human SCC variant.

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    • "Although IKKα deletion in keratinocytes induces spontaneous skin carcinomas, we observe increased IKKα in some human skin SCCs [65,66] (our unpublished data). Immuno-staining reveals that most of the increased IKKα is located in the cytoplasm. "
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    ABSTRACT: Gene knockout studies unexpectedly reveal a pivotal role for IkB kinase alpha (IKKa) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikka heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKa deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikka floxed mice. On the other hand, transgenic mice overexpressing IKKa in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKa represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKa deletion mediated by a mutation, which generates a stop codon in the Ikka gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKa and Ikka mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKa in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.
    Cancers 03/2013; 5(1):170-83. DOI:10.3390/cancers5010170
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    • "Moreover, some unique functions of IKKα that are unrelated to NF-κB activity have also been reported. For example, the studies on IKKα-null mice have revealed that IKKα is essential for the regulation of keratinocyte differentiation and the development of embryonic skin and skin cancers, which cannot be compensated for by IKKβ (16–18,20,21). In addition, IKKα can independently mediate tumor metastasis by inhibiting the transcription of the metastasis suppressor, Maspin (19). "
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    ABSTRACT: Exposure to ultraviolet B (UVB) irradiation from sunlight induces the upregulation of VEGF, a potent angiogenic factor that is critical for mediating angiogenesis-associated photodamage. However, the molecular mechanisms related to UVB-induced VEGF expression have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IκB kinase complex (IKK), IKKα, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKKα kinase activity but is independent of IKKβ, IKKγ and the transactivation of NF-κB. We further show that the transcriptional factor AP-1 functions as the downstream target of IKKα that is responsible for VEGF induction under UVB exposure. Both the accumulation of AP-1 component, c-Fos and the transactivation of AP-1 by UVB require the activated IKKα located within the nucleus. Moreover, nuclear IKKα can associate with c-Fos and recruit to the vegf promoter regions containing AP-1-responsive element and then trigger phosphorylation of the promoter-bound histone H3. Thus, our results have revealed a novel independent role for IKKα in controlling VEGF expression during the cellular UVB response by regulating the induction of the AP-1 component and phosphorylating histone H3 to facilitate AP-1 transactivation. Targeting IKKα shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage.
    Nucleic Acids Research 12/2011; 40(7):2940-55. DOI:10.1093/nar/gkr1216 · 9.11 Impact Factor
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    • "The role of IKKα in cancer development remains controversial: while it has been suggested that it functions as a tumor suppressor in skin cancer [4], [12], [13], there are also evidences that support a role of IKKα as promoter of cancer progression and metastasis in different types of neoplasias such as breast cancer [14], hepatocarcinomas [15], prostate cancer [16], [17] and colorectal cancer [18], [19]. Indeed, we have found, in xenograft assays, an increase in malignancy of skin tumors over-expressing IKKα [5]. "
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    ABSTRACT: Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKKα expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKKα in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKKα transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-α6 and downregulation of the tumor suppressor maspin. Treatment of the back skin of mice with the mitogenic agent 12-O-tetradecanoylphorbol-13-acetate causes in transgenic mice the appearance of different preneoplastic changes such as epidermal atypia with loss of cell polarity and altered epidermal tissue architecture, while in wild type littermates this treatment only leads to the development of benign epidermal hyperplasia. Moreover, in skin carcinogenesis assays, transgenic mice carrying active Ha-ras (K5-IKKα-Tg.AC mice) develop invasive tumors, instead of the benign papillomas arising in wild type-Tg-AC mice also bearing an active Ha-ras. Therefore we provide evidence for a tumor promoter role of IKKα in skin cancer, similarly to what occurs in other neoplasias, including hepatocarcinomas and breast, prostate and colorectal cancer. The altered expression of cyclin D1, maspin and integrin-α6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKKα skin tumors.
    PLoS ONE 07/2011; 6(7):e21984. DOI:10.1371/journal.pone.0021984 · 3.23 Impact Factor
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