Abstract
Lung cancer is the leading cause of cancer-related death in the world. Non-small cell lung carcinomas (Non-SCLC) account for almost 80% of lung cancers, of which 40% were adenocarcinomas. For a better understanding of the molecular mechanisms behind the development and progression of lung cancer, particularly lung adenocarcinoma, we have used proteomics technology to search for candidate prognostic and therapeutic targets in pulmonary adenocarcinoma. The protein profile changes between human pulmonary adenocarcinoma tissue and paired surrounding normal tissue were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-DE) based approach. Differentially expressed protein-spots were identified with ESI-Q-TOF MS/MS instruments. As a result, thirty two differentially expressed proteins (over 2-fold, p<0.05) were identified in pulmonary adenocarcinoma compared to normal tissues. Among them, two proteins (PKM2 and cofilin-1), significantly up-regulated in adenocarcinoma, were selected for detailed analysis. Immunohistochemical examination indicated that enhanced expression of PKM2 and cofilin-1 were correlated with the severity of epithelial dysplasia, as well as a relatively poor prognosis. Knockdown of PKM2 expression by RNA interference led to a significant suppression of cell growth and induction of apoptosis in pulmonary adenocarcinoma SPC-A1 cells in vitro, and tumor growth inhibition in vivo xenograft model (P<0.05). In addition, the shRNA expressing plasmid targeting cofilin-1 significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model. While additional works are needed to elucidate the biological significance and molecular mechanisms of these altered proteins identified in this study, PKM2 and cofilin-1 may serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets for pulmonary adenocarcinoma.
Highlights
Lung cancer was a leading cause of cancer-related death and the 5-year overall survival rate was below 16% [1]
The data presented in this study suggested that both PKM2 and cofilin-1 could be developed as valuable prognostic factors, as well as potential therapeutic targets for lung adenocarcinoma
Tumor non-bearing mice were randomly assigned into the following four groups and each mouse received the corresponding treatment by caudal vein injection: (a) PBS group, 100 ml of PBS; (b) Lipo group, liposome 25 mg; (c) Negative control (NC group), pGenesil-2-HKshRNA 10 mg complexed with liposome 25 mg; (d) PKM2 or cofilin-1-ShRNA group, shRNA 10 mg complexed with liposome 25 mg
Summary
Lung cancer was a leading cause of cancer-related death and the 5-year overall survival rate was below 16% [1]. The development of genome-wide screening have displayed that the initiation, development and outcome of lung adenocarcinomas was associated with DNA methylation [4,5], some genetic mutations, such as K-ras [6,7], p53 [8] and EGFR [9], as well as altered expression of genes, such as VEGF, S100P and crk [10]. These novel biomarkers have been utilized in the diagnosis, prognosis prediction and treatment of lung cancer. The data presented in this study suggested that both PKM2 and cofilin-1 could be developed as valuable prognostic factors, as well as potential therapeutic targets for lung adenocarcinoma
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