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. 2016 Aug 23;7(34):54415-54429.
doi: 10.18632/oncotarget.10074.

Downregulation of the Neonatal Fc Receptor Expression in Non-Small Cell Lung Cancer Tissue Is Associated With a Poor Prognosis

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Free PMC article

Downregulation of the Neonatal Fc Receptor Expression in Non-Small Cell Lung Cancer Tissue Is Associated With a Poor Prognosis

Emilie Dalloneau et al. Oncotarget. .
Free PMC article

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Although the recommended tumor, node and metastasis (TNM) classification and stage determination are important to select therapeutic options for patients with non-small cell lung carcinoma (NSCLC), additional molecular markers are required to indicate the prognosis, in particular within a specific stage, and help with the management of patients.Because neonatal Fc receptor (FcRn) has recently been involved in colon cancer immunosurveillance, we measured its expression in non-cancerous and NSCLC lung tissues and evaluated its prognostic value in overall survival for patient with NSCLC. FcRn expression was determined at both mRNA and protein levels on cancerous and adjacent non-cancerous tissues from 80 NSCLC patients. In NSCLC, FcRn was mainly found in resident and tumor infiltrating immune cells. The corresponding mRNA and protein were significantly less abundant in lung tumor than non-cancerous tissue. Moreover, analysis of our cohort and datasets from the public data bases show that FCGRT mRNA down-regulation is a robust and independent, unfavorable predictive factor of NSCLC patient survival. We conclude that FCGRT mRNA expression may be a useful additional marker for immunoscoring, reflecting tumor immune system, and help in the decision-making process for NSCLC patients.

Keywords: FcRn; antitumor immunity; marker; non-small cell lung cancer; prognosis.

Conflict of interest statement

CONFLICTS OF INTEREST

None.

Figures

Figure 1
Figure 1. A. Ratios of FCGRT mRNA in cancerous (C) / non-cancerous (NC) in paired tissues from the NSCLC patients (n=80; P = 6
27×10−13, Wilcoxon Signed Ranks test). B. Distribution of FCGRT mRNA levels in non-cancerous and cancerous tissues (n=80; P = 2.54×10−21, Mann-Whitney test). C. Representative image of FcRn protein revealed by western blotting in a pool of 10 patients with matched cancerous and adjacent non-cancerous tissue. Recombinant human FcRn protein was loaded as a positive control. Signals were quantified with ImageJ and normalized to that for α-tubulin. D. ROC curve analysis for FCGRT mRNA level in cancerous and non-cancerous lung tissue samples. n= 80, AUC = 0.934, SE = 0.024, 95% CI = 0.884 – 0.967, P < 0.0001, calculations according to DeLong et al., 1988. Youden index J = 0.863 (95% CI = 0.775 – 0.925, BCa bootstrap interval, 1000 iterations). E. ROC curve analysis for FCGRT mRNA levels in stage I cancerous and in non-cancerous tissues (n=37; AUC = 0.947, 95% CI = 0.905 – 0.989, P < 0.001, calculations according to DeLong et al., 1988. Youden index J = 0.871 (95% CI = 0.771 – 0.938, BCa bootstrap interval, 1000 iterations).
Figure 2
Figure 2. Expression of FcRn in non-cancerous A. and cancerous B. serial lung sections from a small set of patients (n=8)
(A) FcRn expression was very week in bronchial epithelial cells (left panel) and marked in alveolar macrophages (right panel) in the non-cancerous lung. (B) In cancerous tissue, the staining revealed that FcRn is expressed in interstitial stromal cells including DCs (PS100), macrophages (CD163) (arrowheads indicate areas of colocalization) but no CD8+ T cells (CD8). A very weak staining was also observed in carcinomatous cells. Pictures from 3 patients were selected as they are representative of the different staining.
Figure 3
Figure 3. A. Kaplan-Meier overall survival analyses for FCGRT mRNA level in cancerous tissue from NSCLC patients (n=71)
Cut-off value = 0.888 (74th percentile of FCGRT mRNA abundance in cancerous samples). B. Kaplan-Meier overall survival analysis for FCGRT mRNA level in non-cancerous tissue from NSCLC patients (n=71). Cut-off value = 2.82 (43th percentile of FCGRT expression in normal tissues). C-D. Kaplan-Meier overall survival analysis for NSCLC patients stratified according to FCGRT mRNA level in cancerous and non-cancerous (n=71). (C) Ch / NCh: Patients with high FCGRT mRNA levels in both tissue parts. Ch / NCl or Cl / NCh: Patients with high FCGRT mRNA expression only in the cancerous or the non-cancerous tissue, respectively. Cl / NCl: Patients with low FCGRT mRNA levels in both tissue parts (n=71). (D) Ch and/or NCh: Patients with high FCGRT mRNA levels in at least one tissue part (cancer and/or non-cancerous tissues n=71). Cl / NCl: Patients with low FCGRT mRNA levels in both tissue parts. Cut-off values as described above.
Figure 4
Figure 4. A. Kaplan-Meier overall survival curves based on FCGRT expression (high vs low), as assessed by the KM plotter expression analysis data
B. Forest plot (random effects method) of the hazard ratio for FCGRT expression and overall survival in lung cancer based on data obtained by the PrognoScan, PROGgeneV2, Kaplan Meier Plotter and SurvExpress platforms. C. Bias assessment plot for trials considered in the meta-analysis.

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