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

Abstract

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.

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

“…Consistent with a role in epidermal homeostasis, IKKa functions as a cofactor for Smad2/ 3 in a Smad4-independent pathway that inhibits keratinocyte proliferation [13,28]. Consequently, IKKa deficient mice display a hyperplasic epidermal phenotype [29,42], whereas animals overexpressing IKKa in the suprabasal skin compartment showed increased epidermal differentiation and are resistant to chemically induced SCC [23]. In the same direction, truncating (inactivating) mutations in the IKKa gene are consistently found in human and mouse SCC lesions [32].…”

“…In the same direction, truncating (inactivating) mutations in the IKKa gene are consistently found in human and mouse SCC lesions [32]. Unexpectedly, we and others recently demonstrated that IKKa activity is significantly increased in a set of human SCC samples [29,30]. We here investigate whether IKK activity influences cSCC behaviour, and which is the effect of targeting IKK in this particular cancer cell type.…”

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

“…Its expression is almost negative in keratinizing nasopharyngeal carcinoma but higher in non-keratinizing nasopharyngeal carcinoma [42]. In epidermal squamous cell carcinomas, IKK1 enhances human keratinocyte differentiation and regulates histological variants [43]. IKK1 is upregulated to control metastasis by repressing maspin in PDAC [44].…”

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…On the contrary, keratin K8, a marker of malignancy in skin tumors (Casanova et al, 2004) showed extensive staining in the C57-CYLD C/S carcinomas and weak expression in the C57-Control tumors (Figure 5a). K13, a keratin characteristic of internal stratified squamous epithelia, which is aberrantly expressed in skin tumors and is also considered a marker of tumor progression (Winter et al, 1990;Moreno-Maldonado et al, 2008) was also highly expressed in the C57-CYLD C/S tumors and it was hardly detected in the C57-Control SCCs (Figure 5a). These data confirm that the tumors arising from C57-CYLD C/S cells are more aggressive that those from control cells.…”