Comparative proteomic approach identifies PKM2 and cofilin-1 as potential diagnostic, prognostic and therapeutic targets for pulmonary adenocarcinoma

PLoS One. 2011;6(11):e27309. doi: 10.1371/journal.pone.0027309. Epub 2011 Nov 8.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Biomarkers, Tumor / analysis*
  • Carrier Proteins / analysis*
  • Carrier Proteins / genetics
  • Cell Proliferation / drug effects
  • Cofilin 1 / analysis*
  • Electrophoresis, Gel, Two-Dimensional
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / chemistry*
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / drug therapy
  • Male
  • Mass Spectrometry
  • Membrane Proteins / analysis*
  • Membrane Proteins / genetics
  • Middle Aged
  • Neoplasm Metastasis / drug therapy
  • Proteomics / methods*
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use
  • Survival Rate
  • Thyroid Hormones / analysis*
  • Thyroid Hormones / genetics
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • CFL1 protein, human
  • Carrier Proteins
  • Cofilin 1
  • Membrane Proteins
  • RNA, Small Interfering
  • Thyroid Hormones
  • thyroid hormone-binding proteins