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Epigenetic Inactivation of IB Kinase- in Oral Carcinomas and Tumor Progression

Authors' Affiliations: Departments of ¹ Biochemistry and ² Oral Surgery, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, Japan; and ³ Department of Oral Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa, Japan

Requests for reprints: Kazushi Imai, Department of Biochemistry, School of Life Dentistry, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan. Phone: 81-3-3261-8870; Fax: 81-3-3261-8875; E-mail: KIMAI{at}Tokyo.ndu.ac.jp.

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. IB kinase- (IKK) has a decisive role in the development of the skin and establishes keratinocyte phenotypes. We assessed clinical implications of IKK expression in oral carcinomas and epigenetic aberrations for the loss of expression.

Experimental Design: We examined IKK 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: IKK 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.

Commentary

Inhibitor-B Kinase in Tumor Promotion and Suppression During Progression of Squamous Cell Carcinoma

Carter Van Waes, Ming Yu, Liesl Nottingham, and Michael Karin
Clin. Cancer Res. 2007 13: 4956-4959. [Full Text] [PDF]

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