The Relationship Of The MTOR Signal Pathway And The Diagnosis Of Non-small Cell Lung Cancer

Background and Objective:Lung cancer is one of the most common cancers worldwide and only a minority of non-small cell lung cancer (NSCLC) patients are suitable for radical therapy including surgery,radiotherapy and chemotherapy as curative care. The PI3K/Akt/mTOR pathway is strongly implicated in human lung cancer. mTOR signaling plays a key role in cell growth, protein translation, autophagy, and metabolism. Activation of mTOR contributes to the pathogenesis of lung cancer. Upstream, phosphatidylinositol 3-kinase (PI3K)/Akt signaling is deregulated through a variety of mechanisms, including overexpression or activation of growth factor receptors such as human epidermal growth factor receptor2(HER-2) and insulin-like growth factor receptor (IGFR), mutations in PI3K and mutations/amplifications of Akt. Tumor suppressor phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a negative regulator of PI3K signaling. PTEN expression is decreased in many cancers. PTEN may be downregulated through several mechanisms, including mutations, loss of heterozygosity, methylation and protein instability. Activation of mTOR results in phosphorylation of its effectors, eukaryotic initiation factor 4E-binding protein 1(4E-BP1) and S6 kinase 1 (S6K1). eIF4E is rate-limiting for capdependent translation. 4E-BP1 hyperphosphorylation leads to inhibition of 4E-BP binding to eukaryotic initiation factor 4E (eIF4E). The purpose of this study was to characterize mTOR,PTEN,IGF-1R,4EBP1 mRNA expression and mTOR,PTEN,IGF-1R protein expression in surgically resected non–small-cell lung cancers (NSCLC) in relation to patient characteristics. Methods:Fifty-four patients with NSCLC who underwent curative pulmonary resection were studied. mTOR,PTEN,IGF1R protein expression was evaluated by immunohistochemistry(IHC) with antibodies . mTOR,PTEN,IGF-1R,4EBP1 gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (RT-PCR) from 54 corresponding fresh-frozen samples.Results:The average mRNA expression levels of mTOR,PTEN,IGF-1R,4EBP1 gene in lung cancer were 0.255±0.175, 0.169±0.161,0.085±0.047,0.097±0.064 respectively, while the mRNA expression levels of mTOR,PTEN,IGF-1R,4EBP1 genes in adjacent-tumor tissue were 0.133±0.090, 0.536±0.390,0.153±0.098,0.112±0.046 respectively. mTOR gene expression in non-small cell lung cancer were significantly higher than that in adjacenttumor lung tissue (P <0.001). PTEN,IGF-1R,4EBP1 gene expression in adjacent tumor tissue were significantly higher than that in lung cancer tissue (P <0.001). The mTOR,PTEN,IGF-1R three-biomarker panel providing 98.15% sensitivity and 88.57% specificity for NSCLC.Conclusions:A significant correlation was observed between expression of average mRNA expression levels of mTOR,PTEN,IGF-1R,4EBP1 gene in lung cancer. A panel of mTOR,PTEN,IGF-1R could serve as a screening strategy for NSCLC.