Epigenetic Inactivation of IκB Kinase-α in Oral Carcinomas and Tumor Progression

Abstract

Purpose: 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. InB kinase-a (IKKa) has a decisive role in the development of the skin and establishes keratinocyte phenotypes.We assessed clinical implications of IKKa expression in oral carcinomas and epigenetic aberrations for the loss of expression. Experimental Design: We examined IKKa 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: IKKa 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. Conclusion: 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.

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

“…Here, we have exploited the marked reduction in IKK␣ expression and failure to shuttle to the nucleus exhibited in poorly differentiated human SCCs, combined with gene profiling, to unveil an explanation for the previously documented tumor-suppressive function of IKK␣ (15,16). We provide evidence for a role for IKK␣ in regulation of TGF-␤-activated cytostatic responses in keratinocytes, and have translated these observations to human tumor cell models to explain how IKK␣ acts as a tumor suppressor in SCC derived from stratified epithelia.…”

“…A tumor-suppressive role for IKK␣ in SCC was recently identified in a mouse model of chemically induced SCC and a small number of human samples (15). More recent evaluation of IKK␣ expression in SCC revealed its loss in about 30% of such cancers, especially in those that develop a highly invasive phenotype (16). It is not clear, however, how IKK␣ exerts its tumor-suppressive activity in human SCC, and different possible modes of action were recently discussed (17).…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[7,9,10] Alternatively, IKKα suppresses carcinogenesis in the skin, lungs, esophagi, nasopharynges, and pancreas of humans and mice independently of canonical and noncanonical NF-kB pathways ( Figure 1B). [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] These findings highlight the medical importance of IKK/NF-kB in the pathogenesis of human diseases and malignancies.…”

“…Severe autoimmunity and systemic autoinflammation Tumors in the esophagus and oral cavity/ fungal infection [25,35,36] Skin, lung, esophgeal, oral, and pancreatic cancer [15][16][17][18][19][20][21][22][23][24][25][26][27][28] www.advancedsciencenews.com www.bioessays-journal.com NF-kB pathways. [1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers.…”

IKKα represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin

“…Several laboratories have demonstrated that IKKa expression was downregulated, or that its localization was altered in human squamous cell carcinomas of the skin, lungs, and head and neck, [16][17][18][19][20] highlighting the importance of IKKa in human malignancy development. We showed that induced IKKa deletion in keratinocytes causes epidermal hyperplasia and spontaneous skin tumors.…”