Epigenetic inactivation of IkappaB Kinase-alpha in oral carcinomas and tumor progression.
OBJECTIVE
The loss of epithelial phenotypes in the process of carcinoma progression correlates with clinical outcome, and genetic/epigenetic changes accumulate aggressive clones toward uncurable disease. IkappaB kinase-alpha (IKKalpha) has a decisive role in the development of the skin and establishes keratinocyte phenotypes. We assessed clinical implications of IKKalpha expression in oral carcinomas and epigenetic aberrations for the loss of expression.


METHODS
We examined IKKalpha expression in oral carcinomas by immunostaining (n = 64) and genetic instability by microsatellite PCR (n = 46). Promoter methylation status was analyzed by bisulfite-modified sequence (n = 11).


RESULTS
IKKalpha was expressed in the nucleus of basal cells of normal oral epithelium, but not or marginally detected in 32.8% of carcinomas. The immunoreactivity was significantly decreased in less differentiated carcinomas (P < 0.05) and correlated to long-term survival of patients (P < 0.01) with an independent prognostic value (P < 0.05). Although allelic/biallelic loss of the gene was limited to four cases, we detected microsatellite instability in 63.0% cases in which the immunoreactivities were decreased and the promoter was hypermethylated.


CONCLUSIONS
These results showed that oral carcinomas exhibiting genetic instability and promoter hypermethylation down-regulate expression of IKK and suggest that the epigenetic loss of the expression closely associates with disease progression toward unfavorable prognosis.
Maeda
Genta
G
Department of Biochemistry, School of Life Dentistry, Nippon Dental University, Tokyo, Japan.
Chiba
Tadashige
T
Kawashiri
Shuichi
S
Satoh
Tazuko
T
Imai
Kazushi
K
D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic