Abstract 5382: LKB1 downregulation in head and neck cancer is independent of promoter methylation or FOXO3 expression.

Abstract

Abstract Cancers of the head and neck comprise a diverse group of tumors with squamous cell carcinoma (HNSCC) as the predominant form. Epidemiological data suggest that the etiology and pathogenesis of HNSCC are influenced by environmental and life-style-related factors, such as tobacco use, dietery factors and exposure to toxic substances. However, only a small fraction of tobacco users develop HNSCC suggesting that genetic factors may play a key role in the development of HNSCC. Therefore, genetic abnormalities in HNSCC have been studied extensively. The genetic changes associated with HNSCC affect a variety of different pathways and vary from point mutations to chromosomal aberrations which impair the function or expression of both oncogenes and tumor suppressor genes. Liver Kinase B1 (LKB1) is one of the recently identified tumor suppressor genes which is mutated in Peutz-Jeghers syndrome. It codes for a well-conserved serine-threonine kinase and regulates multiple biological processes and signaling pathways including the control of cell-cycle arrest, p53-mediated apoptosis, Wnt signaling, TGF-ß-signaling, ras-induced cell transformation and energy metabolism. Somatic LKB1 alterations have been reported in a variety of carcinomas. Different studies have shown that the LKB1 protein can be inactivated by a wide spectrum of mutations that are scattered all over the protein or by promoter methylation in different types of cancer. Recently, it has been reported that LKB1 is transcriptionally regulated by binding of the FOXO3 protein to the cis-regulatory elements in the promoter region of the LKB1 gene. The FOXO proteins can affect a wide range of biological processes such as cell cycle, stress resistance, development, reproduction, and ageing. In this study we investigated the effect of FOXO3 in the silencing of LKB1 expression in head and neck cancer. For this purpose LKB1 and FOXO3 expression levels and methylation status of the LKB1 promoter were analyzed by real-time PCR and methylation-specific PCR in LKB1-mutant and wild-type HNC tumor samples and matched normal tissue from 49 patients with HNSCC. The average decrease in FOXO3 mRNA expression in the tumor samples was 40%. Downregulation of LKB1 mRNA expression was also observed in a similar fraction of the patients (44%). However, the association was not statistically significant. We observed partial promoter methylation only in 3 of the tumor samples. LKB1 mRNA was downregulated particularly in grade IV tumors indicating that alterations of LKB1 take place during the later stages of HNC carcinogenesis. Our results suggest that LKB1 downregulation is not the result of promoter methylation or modulation by FOXO3. Therefore, the exact understanding of the regulation of LKB1 and FOXO3 in HNSCC requires further studies. Citation Format: Nejat Dalay, Seda Ekizoglu, Emin Karaman, Demet Akdeniz, Ahmet Ozaydin, Nur Buyru. LKB1 downregulation in head and neck cancer is independent of promoter methylation or FOXO3 expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5382. doi:10.1158/1538-7445.AM2013-5382