The role of PKR/eIF2α signaling pathway in prognosis of non-small cell lung cancer - PubMed (original) (raw)

doi: 10.1371/journal.pone.0024855. Epub 2011 Nov 10.

Arlene M Correa, Maria Gabriela Raso, Wayne L Hofstetter, Bingliang Fang, Carmen Behrens, Jack A Roth, Yihong Zhou, Liping Yu, Ignacio I Wistuba, Stephen G Swisher, Apar Pataer

Affiliations

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

Yong He et al. PLoS One. 2011.

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.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts. LY is an employee of Ziren Research LLC. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1

Figure 1. PKR mRNA levels are correlated with PKR protein levels in primary NSCLC tissues.

A. Western blot analysis of PKR and p-PKR protein in tumor samples. A densitometric analysis of the ratio of PKR or PKR to β-actin is represents normalized protein levels. Each lane represents a tumor sample from an individual patient. B. mRNA levels of corresponding samples were determined using quantitative real-time PCR. Levels of β-actin protein and its mRNA of the same sample were used as controls. C. Scatter plot of PKR protein expression correlated with mRNA expression (Spearman's rho = 0.55, p<0.001).

Figure 2

Figure 2. Representative results of immunohistochemical staining of NSCLC tumor specimens for p-PKR and p-eIF2α.

High-expressing cases (A and C). Low-expressing cases (B and D). Expression of p-PKR and p-eIF2α was detected in the cytoplasm.

Figure 3

Figure 3. The prognostic significance assessed by using Kaplan-Meier survival estimates and long-rank test.

A–F. Kaplan-Meier survival curves according to the differences in (A, B, C) p-PKR and (D, E, F) p-eIF2-α expression in patients with stage I (A, D), stages II–IV (B, E) and all stage (C, F) NSCLC. The survival rates were significantly worse in the patients with low p-PKR or p-eIF2α expression than in those with high p-PKR or p-eIF2α expression (Stage I: p = 0.01 and p = 0.02; All stages: p = 0.03 and p = 0.03, respectively).

Figure 4

Figure 4. The prognostic significance assessed by using Kaplan-Meier survival estimates and long-rank test.

A and C. Survival rate was significantly lower patients with low PKR or low p-PKR expression than in those with high PKR or high p-PKR expression on stage I (A) and all stages (C) (p = 0.001 and p = 0.001, respectively). B and D. Survival rate was also significantly lower in patients with low PKR or low p-eIF2α expression than in those with high PKR or high p-eIF2α expression on stage I (B) and all stages (D) (p = 0.001 and p = 0.001, respectively).

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