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Brief Report

Long non-coding RNA LINC00987 may function as a tumor suppressor in lung adenocarcinoma

[version 1; peer review: 1 approved with reservations, 1 not approved]
PUBLISHED 04 May 2018
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Abstract

Long non-coding RNAs (lncRNAs) are a group of transcripts over 200 nucleotides in length that do not code for proteins. The association of the dysregulation of numerous lncRNAs with several malignancies, including lung cancer, has been frequently reported. This study aims to inspect the association of genomic and transcriptomic alterations to the lncRNA LINC00987 with lung adenocarcinoma, a subtype of lung cancer, using a bioinformatic approach. To this end, we used three publically available online databases, cBioPortal, the International Cancer Genome Consortium Data Portal and the GEPIA web server. In short, our results demonstrated that LINC00987 expression might have a tumor suppressive role in lung adenocarcinoma and levels of expression could be of prognostic value for this cancer type.

Keywords

LINC00987, Lung adenocarcinoma, Tumor suppressor lncRNA, Genotranscriptomic analysis, Bioinformatics

Introduction

Lung cancer is the leading cause of cancer-related death in the world among both men and women1. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and accounts for over a million cancer-related deaths each year2,3. Thus, the identification of molecules involved in the initiation and development of LUAD should be a high priority and could help the early diagnosis, prognosis, and treatment of this lethal cancer.

Long non-coding RNAs (lncRNAs) are a subclass of non-protein-coding transcripts over 200 nucleotides in length that are involved in several cancer-related biological processes, including cell growth, cell proliferation, and apoptosis4,5. It has been frequently reported that lncRNAs, due to their pivotal regulatory roles in the cellular events, especially cell cycle processes, can be used as cancer biomarkers6. HOTAIR, for example, is an oncogenic lncRNA that is being used as a biomarker for several cancers7. LINC00987 is a poorly known lncRNA that has been observed to be dysregulated in LUAD by microarray studies8. However, the genomic and transcriptomic alterations to LINC00987 lncRNA in LUAD have not yet been precisely examined.

In this study, we investigated the association of LINC00987 genomic and transcriptomic alterations with LUAD. Moreover, the relationship between the LINC00987 expression level and the overall survival (OS) of LUAD patients was inspected. To accomplish these goals, three well-known online databases, cBioPortal, the International Cancer Genome Consortium (ICGC) Data Portal and the GEPIA web server, were employed.

Methods

Genomic analysis

Copy number alterations in LINC00987 lncRNA across The Cancer Genome Atlas (TCGA) LUAD study (586 samples) were retrieved from the cBioPortal database9,10. To this end, the “Putative copy-number alterations from GISTIC” and “All Tumors (586)” were selected as the genomic profile and the patient/case set, respectively. The Gene-level Analysis tool of the TCGA Copy Number Portal (Analysis Version: 2015-06-01 stddata__2015_04_02 regular peel-off)11 was used to determine whether LINC00987 is located within or near any peak region of somatic copy-number alterations in LUAD (516 samples). TCGA Copy Number Portal facilitates the understanding of high resolution copy number data amassed from cancer samples in the TCGA. Furthermore, the mutations to LINC00987 lncRNA in LUAD was analyzed by means of the ICGC Data Portal (https://dcc.icgc.org) To this purpose, the “LINC00987” term was searched in the ICGC Data Portal and the projects related to the LUAD were selected from the results.

Transcriptomic analysis

The GEPIA web server12 was used to investigate the differential expression of LINC00987 lncRNA between LUAD tumor (#483) and normal (#347) samples. To this end, the Differential Expression Analysis and the Expression DIY Boxplot tools were employed with default options. The association of the differential expression of the LINC00987 lncRNA with the OS of LUAD patients was examined using the Survival Plots tool of the GEPIA web server with default parameters.

Results

LINC00987 has genomic alterations in LUAD

Copy number alteration analysis of LINC00987 demonstrated that this lncRNA was deeply deleted in over 4 percent of LUAD sequenced cases/patients (Figure 1a). However, LINC00987 lncRNA was amplified in 5 out of 230 LUAD sequenced samples. Analysis of somatic copy-number alterations to LINC00987 demonstrated that this lncRNA is located within a focal peak region of deletion (chr12:2782810-17821101) in LUAD (overall frequency of deletion: 0.2578; q-value: 0.0802). In addition, our results indicated that LINC00987 was mutated in 6.06% of LUAD donors, including chr12:g.9392556T>C, chr12:g.9392654T>C, and chr12:g.9393053C>G, according to the LUNG CANCER - KR project.

73fbcfd3-45ae-4499-ba3e-bbae0c8741b9_figure1.gif

Figure 1. Genomic and transcriptomic alterations of LINC00987 long non-coding RNA (lncRNA) in lung adenocarcinoma (LUAD).

(a) Copy number alterations of LINC00987 in LUAD according to the The Cancer Genome Atlas data (230 sequenced samples). Red, blue, and gray colors are indicative of amplified (n=10), deleted (n=5), and non-altered (n=215) samples, respectively. Cumulatively, 7% (n=15) of the sequenced samples had copy number alterations. The figure was retrieved from the cBioPortal database. (b) Dysregulation of LINC00987 lncRNA in LUAD. The asterisk indicates the extreme outliers. The figure was created using Boxplot function in Expression DIY of the GEPIA web server. (c) The association of LINC00987 expression level with the overall survival of LUAD patients. The figure was created using the GEPIA web server.

LINC00987 is downregulated in LUAD

Transcriptomic analysis of LINC00987 using the GEPIA web server showed that this lncRNA was significantly downregulated (log2(fold change) = −1.225; adjusted p-value = 1.17e−129) in LUAD (Figure 1b). Survival analysis indicated that the expression level of LINC00987 is significantly related (log-rank p-value = 0.0023) to the OS of LUAD patients (Figure 1c).

Dataset 1.The copy number alteration raw data, retrieved from the cBioPortal database.

Discussion

The aim of this study was to examine the association of genotranscriptomic alterations of LINC00987 lncRNA with LUAD using a bioinformatic approach. There is an increasing number of publications revealing the key roles of lncRNAs in cancer development and their potential as cancer biomarker.

According to our results, LINC00987 lncRNA is deleted in a significant proportion of the LUAD cases. LINC00987 was mutated in over 6 percent of LUAD patients. Frequent deletion and functional mutations are characteristic of dysregulated tumor suppressor genes in cancer1315. LINC00987 lncRNA is under-expressed in LUAD samples compared with normal samples. Furthermore, survival analysis indicated that downregulation of LINC00987 lncRNA is associated with a lower OS period in LUAD patients. These cues, (that is, the under-expression of LINC00987 in cancer and the positive association of its expression level with OS of cancer patients) are characteristic of tumor suppressor genes in cancer.

Overall, LINC00987 may be a tumor suppressive lncRNA in LUAD and could be considered as a biomarker for the diagnosis and/or prognosis of patients with this cancer type. However, further bioinformatic and experimental studies are required to decipher the precise function of LINC00987 in lung tissue and evaluate its application as a biomarker for LUAD.

Data availability

Dataset 1. The copy number alteration raw data, retrieved from the cBioPortal database. DOI: 10.5256/f1000research.14785.d20256316.

All of the results presented in this study can be directly achieved using the procedures described in the Methods section.

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Salavaty A, Rezvani Z and Najafi A. Long non-coding RNA LINC00987 may function as a tumor suppressor in lung adenocarcinoma [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2018, 7:540 (https://doi.org/10.12688/f1000research.14785.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 04 May 2018
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Reviewer Report 31 Aug 2018
Wen Cai Zhang, Department of Pathology,  Beth Israel Deaconess Medical Center/Harvard Medical School,  Boston, MA, USA 
Approved with Reservations
VIEWS 9
The authors found that LINC00987 is a new long non-coding RNA which is poorly known in lung adenocarcinoma. Using genomic and transcriptomic databases, the authors discovered that LINC00987 is a tumor suppressive non-coding RNA and its expression levels correlate with ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Zhang WC. Reviewer Report For: Long non-coding RNA LINC00987 may function as a tumor suppressor in lung adenocarcinoma [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2018, 7:540 (https://doi.org/10.5256/f1000research.16089.r36973)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 07 Jun 2018
Antonio Marco, School of Biological Sciences, University of Essex, Colchester, UK 
Not Approved
VIEWS 31
The authors explored major databases of genomic alterations in cancer samples and evaluated a potential role of LINC00987 in Lung Adenocarcinoma.

They concluded that their results "demonstrate that LINC00987 expression might have a tumor suppressive role in ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Marco A. Reviewer Report For: Long non-coding RNA LINC00987 may function as a tumor suppressor in lung adenocarcinoma [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2018, 7:540 (https://doi.org/10.5256/f1000research.16089.r34549)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 08 Jun 2018
    Abbas Salavaty, Division of Biotechnology, Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
    08 Jun 2018
    Author Response
    1. We agree with you about the clarification of gene nomenclature. Actually, LINC00987 was previously known as LOC100499405. Please take a look at row 817 of the Table S5
    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 08 Jun 2018
    Abbas Salavaty, Division of Biotechnology, Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
    08 Jun 2018
    Author Response
    1. We agree with you about the clarification of gene nomenclature. Actually, LINC00987 was previously known as LOC100499405. Please take a look at row 817 of the Table S5
    ... Continue reading

Comments on this article Comments (0)

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VERSION 1 PUBLISHED 04 May 2018
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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