The role of PKR/eIF2α signaling pathway in prognosis of non-small cell lung cancer

PLoS One. 2011;6(11):e24855. doi: 10.1371/journal.pone.0024855. Epub 2011 Nov 10.

Abstract

Background: In this study, we investigated whether PKR protein expression is correlated with mRNA levels and also evaluated molecular biomarkers that are associated with PKR, such as phosphorylated PKR (p-PKR) and phosphorylated eIF2α (p-eIF2α).

Methodology and findings: We determined the levels of PKR protein expression and mRNA in 36 fresh primary lung tumor tissues by using Western blot analysis and real-time reverse-transcriptase PCR (RT-PCR), respectively. We used tissue microarrays for immunohistochemical evaluation of the expression of p-PKR and p-eIF2α proteins. We demonstrated that PKR mRNA levels are significantly correlated with PKR protein levels (Spearman's rho = 0.55, p<0.001), suggesting that PKR protein levels in tumor samples are regulated by PKR mRNA. We also observed that the patients with high p-PKR or p-eIF2α expression had a significantly longer median survival than those with little or no p-PKR or p-eIF2α expression (p = 0.03 and p = 0.032, respectively). We further evaluated the prognostic effect of combined expression of p-PKR plus PKR and p-eIF2α plus PKR and found that both combinations were strong independent prognostic markers for overall patient survival on stage I and all stage patients.

Conclusions: Our findings suggest that PKR protein expression may controlled by transcription level. Combined expression levels of PKR and p-PKR or p-eIF2α can be new markers for predicting the prognosis of patients with NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Eukaryotic Initiation Factor-2 / genetics*
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Male
  • Phosphorylation
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survival Rate
  • eIF-2 Kinase / genetics*
  • eIF-2 Kinase / metabolism*

Substances

  • Eukaryotic Initiation Factor-2
  • RNA, Messenger
  • eIF-2 Kinase