Silencing of the cell cycle checkpoint gene 14-3-3σ in basal cell carcinomas correlates with reduced expression of IKK-α.
BACKGROUND
14-3-3σ is down-regulated in a large proportion of basal cell carcinomas (BCC). IkappaB kinase α (IKK-α), 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-α causes hyperplasia and promotes skin cancer. IKK-α has been found to regulate the expression of 14-3-3σ by shielding its promoter from hypermethylation and thereby preventing its silencing in mouse keratinocytes.


OBJECTIVE
To evaluate the potential role of IKK-α in the silencing of 14-3-3σ in basal cell carcinoma.


METHODS
Expression of 14-3-3σ and IKK-α 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 14-3-3σ was found in 24 (92%) BCCs from BCNS patients, and in 29 (88%) sporadic BCCs. Marked reduction or absence of IKK-α was found in 22 (85%) BCCs from patients with BCNS, and in 27 (82%) sporadic BCCs. Expression levels for 14-3-3σ and IKK-α correlated positively in 92% of BCCs from BCNS patients, and in 85% of sporadic BCCs.


CONCLUSIONS
Our findings suggest that down-regulation of IKK-α is required for 14-3-3σ promoter methylation and silencing in the pathogenesis of BCC. Besides, our observation that 14-3-3σ silencing is also frequently found in BCC from patients with BCNS suggests a possible link between the sonic hedgehog/patched and 14-3-3σ/IKK-α pathways.
Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig Maximilian University, Munich, Germany.
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Molin
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Grgic
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Ruzicka
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Herzinger
D048948:14-3-3 Proteins / Q000235:genetics*; D002280:Basal Cell Carcinoma / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D012878:Skin Neoplasms / Q000235:genetics*
D048948:14-3-3 Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha