No abstract

Head and neck cancer is a multifactorial disease including a group of biologically similar cancers and representing 3% of all malignant tumors. Its incidence has been rising in the last years with more than half a million cases and leading to 300 000 deaths yearly. The most common tumor type is squamous cell carcinoma but recent studies have shown that the tumors may display a very heterogenous nature. Although the survival rates have improved over the past decades due to the use of concurrent therapeutic modalities the molecular mechanism of the disease is still obscure. Besides tobacco and alcohol consumption several other factors including viral infection, diet, inflammation and occupational or genetic factors have been implicated with the disease. Recent findings suggest an important role for genetic factors in head and neck carcinogenesis. Alterations in the signaling pathways leading to the activation of oncogenes and inhibition of tumor suppressor genes are being increasingly implicated with the development of the disease. Head and neck cancer is associated with the enhanced expression and activity of different signaling pathways which lead to phosphorylation of several kinases and activation of a number of transcription factors. In order to better understand the molecular mechanisms of head and neck carcinogenesis it is essential to characterize the molecular changes and their involvement in the alterations of the cellular control. One of the key signaling pathways in head and neck cancer is the PI3K-Akt-MTOR pathway which has a crucial role in cell growth and survival. Dysregulation of this pathway generates a favourable oncogenic environment, and has been documented in a variety of transformed cells and human tumors. PIK3CA and Akt are critical genes in the PI3K signaling pathway. It has been shown that exons 9 and 20 of the PIK3CA gene are frequently mutated in various cancers. On the other hand, elevated expression of phosphorylated Akt reflects PI3K pathway activation. It has also been known that the master kinase LKB1 is a tumor suppressor and exerts its effect on multiple signaling pathways. Therefore, in this study we investigated the effect of LKB1on the mRNA expression levels and PIK3CA mutations in relation to the Akt phosphorylation rate in HNSCC. For this purpose, we analyzed LKB1, PIK3CA and Akt1 expression levels by qRT-PCR in association with PIK3CA exon 9 and 20 mutations and p-Akt levels in 100 HNSCC tumors and corresponding non-cancerous tissue samples. Down-regulation of the LKB1 mRNA expression level was observed in 63.3% of the cases and this down-regulation was associated with Akt1 phosphorylation. Our results indicate that activation of PI3K pathway is significantly associated with the down-regulation of LKB1. Citation Format: Nejat Dalay, Seda Ekizoglu, Soydan Dogan, Emin Karaman, Damla Ulker, Nur Buyru. LKB1 loss is associated with Akt1 phosphorylation in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A14.

Our results indicate that the PI3K pathway has an important function in HNSCC progression with the contribution of more than one gene of this pathway. Our data suggest that in a high number of HNSCC tumours, PI3K/Akt signalling is activated by different molecules or by the combination of these molecules.