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IKKα enhances human keratinocyte differentiation and determines the histological variant of epidermal squamous cell carcinomas

Rodolfo Moreno-Maldonado, Angel Ramírez, Manuel Navarro, M. Jesús Fernández-Aceñero, Concepción Villanueva, Angustias Page, José L. Jorcano, Ana Bravo and M. Llanos Casanova

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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 (IκB kinase) α 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 IKKα expression increases both early and terminal differentiation of human keratinocytes through an E-cadherin-dependent mechanism. Increased expression of IKKα 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 IKKα murine tumors, express high levels of both IKKα and E-cadherin, with absence of keratins K1 and K10, usually co-expressed with IKKα and E-cadherin. The tight correlation between the properties of both murine and human ASCC variants strongly suggests that IKKα is responsible for the development of this human SCC variant.

Authors

Rodolfo Moreno-Maldonado

CIEMAT; Madrid, Spain

Angel Ramírez

CIEMAT; Madrid, Spain

Manuel Navarro

CIEMAT; Madrid, Spain

M. Jesús Fernández-Aceñero

Hospital de Móstoles; Madrid, Spain

Concepción Villanueva

Hospital de Móstoles; Madrid, Spain

Angustias Page

CIEMAT; Madrid, Spain

José L. Jorcano

CIEMAT; Madrid, Spain

Ana Bravo

University of Santiago de Compostela; Lugo, Spain

M. Llanos Casanova

CIEMAT; Madrid, Spain

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.