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. 2017 Oct 27;11(13):1172-1185.
eCollection 2020 Mar 31.

The Value of lncRNA FENDRR and FOXF1 as a Prognostic Factor for Survival of Lung Adenocarcinoma

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Free PMC article

The Value of lncRNA FENDRR and FOXF1 as a Prognostic Factor for Survival of Lung Adenocarcinoma

Antonio Herrera-Merchan et al. Oncotarget. .
Free PMC article

Abstract

It is increasingly evident that non-coding RNAs play a significant role in tumour development. However, we still have a limited knowledge of the clinical significance of long non-coding RNAs (lncRNAs) in lung cancer. The FENDRR is a long coding RNA (also named FOXF1-AS1) located in the vicinity of the protein-coding gene FOXF1 at 16q24.1 chromosomal region. The present study aimed to define the clinic pathological significance of the long-non-coding RNA FENDRR in lung adenocarcinomas. FENDRR expression measured by quantitative PCR was found significantly downregulated (p<0.001) in lung adenocarcinoma samples in comparison with their normal adjacent tissues (n=70). RNA in situ hybridization (RNA-FISH) corroborated independently the down-regulation of FENDRR. Interestingly, the expression of FENDRR correlated positively (p<0.001) with the expression of its protein-coding neighbor gene FOXF1. Additionally, FOXF1 expression was also found downregulated in adenocarcinomas compared to normal samples (p<0.001) and its expression was significantly correlated with overall survival alone (p=0.003) or in combination with FENDRR expression (p=0.01). In conclusion, our data support that FENDRR and FOXF1 expression is decreased in lung adenocarcinoma and should be considered as new potential diagnostic/prognosis biomarkers.

Keywords: FENDRR; FOXF1; lncRNA; lung cancer; methylation.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. FENDRR and FOXF1 mRNAs are significant biomarkers of lung adenocarcinoma (LUAD).
(A) FENDRR and FOXF1 expression was analyzed by qRT-PCR in 70 LUAD and 70 normal lung tissues. FENDRR and FOXF1 were significantly downregulated in lung adenocarcinomas versus their adjacent normal lung tissues. (B) The expression levels of FENDRR and FOXF1 was positive correlated in each other in lung tumor and adjacent normal lung tissues (Pearson's coefficient = 0.622, p<0.001).
Figure 2
Figure 2. FENDRR expression detection by RNA-FISH in lung cancer and normal lung.
RNA FENDRR fluorescence in situ hybridization (RNA-FISH) in two representative pairs of primary lung adenocarcinoma (A, C) and adjacent normal tissue (B, D). Red: FENDRR probe, bluet: DAPI.
Figure 3
Figure 3. Kaplan-Meier survival analysis for the relationship between survival time and FENDRR and FOXF1 signature in lung adenocarcinomas.
Higher FENDRR and FOXF1 expression was associated with a better overall survival for patients with lung cancer. The survival function is defined as the probability of surviving at least to the time determined in x-axis (in months).
Figure 4
Figure 4. Identification process of somatic variants in FENDRR and FOXF1.
(A) Schematic of bioinformatics SNV detection workflow. (B) Extraction of functionally relevant somatic mutations for FOXF1 and FENDRR in lung cancer. Variants were filtered for annotation in dbSNP, 1000genomes, ExAC, NCI60, somatic and functionally impairment. From dbSNP or the 1000 genomes variants with frequencies above 1% were excluded.
Figure 5
Figure 5. Epigenetic inactivation of FENDRR and FOXF1 in lung adenocarcinoma.
(A) Graphic obtained from Wanderer data base (http://maplab.imppc.org/wanderer/) of all CpGs island of FENDRR and FOXF1 and their percentage of DNA methylation in lung cancer (medium of 463 samples, brown) and normal lung (medium of 32 samples, blue). In x-axis the cg# indicates the position of the CpG island. *: indicates differences statistically significant between normal and tumor samples. (B) Percentage of DNA Methylation in the FOXF1 promoter in 5 lung cancer cells lines by bisulphite sequencing. Hypermethylation of FOXF1 promoter was detected in 2 of 5 cell lines (H441 and H838).
Figure 6
Figure 6. FENDRR and FOXF1 relationship determined by luciferase assays in the A549 cell line.
(A) Normalized luciferase expression comparing the luciferase reporter under FOXF1 promoter with and without methylation after adding FENDRR. Error bars represent standard deviation. (B) Control: Normalized luciferase expression comparing the reporters under the FOXF1 promoters with and without methylation after FENDRR transfection. FENDRR: expression plasmid of FENDRR. Control: expression plasmid where FENDRR has been substituted by GFP.

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