Co-expression Of β-arrestinl And NF-κB Is Associated With Poor Prognosis In Lung Adenocarcinoma

Background:Lung cancer is the most common and lethal carcinoma all over the world and often diagnosed at an advanced stage with poor prognosis. Approximately 80% of lung cancers are non-small cell lung cancer (NSCLC) and adenocarcinoma is the most common histologic subtype. Beta-arrestins, ubiquitously expressed in virtually all tissues of mammals, are a class of intracellular protein and composed of β-arrestinl and β-arrestin2. Beyond their well-characterized roles in G protein-coupled receptors (GPCRs) desensitization and trafficking, β-arrestins also serve as multi-functional adaptors and scaffolds in modulating a variety of intracellular signal networks, which contribute to regulate several cancer cell phenotypes, including cancer cell proliferation, migration, invasion and metastasis. NF-κB is a universally expressed transcription factor complex that has been shown to be involved in immunity, inflammation, antiapoptotic and tumorigenesis. A recent report identified a novel nuclear localization sequence in β-arrestinl, which mediated active transport of β-arrestinl into the nucleus. Moreover, recent research suggested that β-arrestinl could directly combine with p65 thereby forming a nuclear complex in the nucleus, that might be critical for its ability to potentiate NF-κB transcriptional activity. On the basis of mentioned analysis above, we speculate that β-arrestinl enhanced NF-κB nuclear activation may have a considerable effect on cancer cell proliferation, apoptosis, invasion and metastasis. Thus far, there is nevertheless little study about these two molecules in lung adenocarcinoma.Purposes:The aim of this study was to investigate the correlation between β-arrestinl and NF-κB expression and the clinicopathological characteristics in lung adenocarcinoma, and to determine whether combined expression of β-arrestinl and p65 have a more valuable prognostic significance.Methods:A total of 115 patients with primary lung adenocarcinoma who had undergone complete surgical resection were obtained in this study. Specimens were collected from patients in Department of Thoracic Surgery of Shandong Provincial Hospital Affiliated to Shandong University from June 2008 to December 2009. Expression of β-arrestin1 and p65 were detected by immunohistochemistry (IHC) in lung adenocarcinoma tissue samples. Survival analysis and curves were established using the Kaplan-Meier method and the log-rank test was used to estimate differences in survival. Cox proportional hazard model were then performed to determine the relationship between expression of β-arrestinl and p65 and the clinical characteristics and to analyze whether co-expression of nuclear β-arrestinl and p65 was a significant independent prognostic factor for lung adenocarcinoma patients.Results:Nuclear expression of β-arrestinl and p65 were observed in 39.1%(45/115) and 46.1%(53/115) cases of lung adenocarcinoma, respectively. And high expression of β-arrestinl had negative prognostic impact for overall survival (OS) and disease-free survival (DFS) (p=0.034 and p=0.033). In addition, overexpression of p65 indicated a significantly poor OS and DFS than those of lower-expression (p=0.038 and p=0.041). Furthermore, co-expression of nuclear β-arrestinl and p65 correlated with poorer OS and DFS in lung adenocarcinoma patients. Multivariate analysis using the Cox regression model confirmed that co-expression of nuclear β-arrestinl and p65 was an independent prognostic factor for tumor progression (p=0.008).Conclusion:Our study demonstrates that β-arrestinl and p65 are overexpressed in the nucleus of lung adenocarcinoma tissues. Moreover, co-overexpression of these two molecules is associated with poor malignant tendency of lung adenocarcinoma patients. These results provide evidences that the co-expression of β-arrestinl and p65 is potentially involved in the progression and prognosis of lung adenocarcinoma, which indicated that these proteins should be considered as molecular biomarkers of lung adenocarcinoma diagnosis and prognosis, as well as targets for more efficient treatment.