Silencing of the cell cycle checkpoint gene 14-3-3σ in basal cell carcinomas correlates with reduced expression of IKK-α

Background 14-3-3 sigma is down-regulated in a large proportion of basal cell carcinomas (BCC). IkappaB kinase alpha (IKK-alpha), one of the two catalytic subunits of the IKK complex involved in NF-kappaB-activation, also functions as a modulator of epidermal development and differentiation. Down-regulation of IKK-alpha causes hyperplasia and promotes skin cancer. IKK-alpha has been found to regulate the expression of 14-3-3 sigma by shielding its promoter from hypermethylation and thereby preventing its silencing in mouse keratinocytes. Objectives To evaluate the potential role of IKK-alpha in the silencing of 14-3-3 sigma in basal cell carcinoma. Materials and methods Expression of 14-3-3 sigma and IKK-alpha was studied by immunohistochemistry in 33 sporadic BCCs and 26 BCCs from patients with basal cell nevus syndrome (BCNS). Results Marked reduction or absence of 14-3-3 sigma was found in 24 (92%) BCCs from BCNS patients, and in 29 (88%) sporadic BCCs. Marked reduction or absence of IKK-alpha was found in 22 (85%) BCCs from patients with BCNS, and in 27 (82%) sporadic BCCs. Expression levels for 14-3-3 sigma and IKK-alpha correlated positively in 92% of BCCs from BCNS patients, and in 85% of sporadic BCCs. Conclusions Our findings suggest that down-regulation of IKK-alpha is required for 14-3-3 sigma promoter methylation and silencing in the pathogenesis of BCC. Besides, our observation that 14-3-3 sigma silencing is also frequently found in BCC from patients with BCNS suggests a possible link between the sonic hedgehog/patched and 14-3-3 sigma/IKK-alpha pathways.