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. 2019 Feb;41(2):895-907.
doi: 10.3892/or.2018.6870. Epub 2018 Nov 15.

Pathway analysis of a genome‑wide association study on a long non‑coding RNA expression profile in oral squamous cell carcinoma

Yong-Le Qiu  1 , Yuan-Hang Liu  2 , Jian-Dong Ban  3 , Wen-Jing Wang  1 , Mei Han  4 , Peng Kong  4 , Bing-Hui Li  1
Affiliations

Pathway analysis of a genome‑wide association study on a long non‑coding RNA expression profile in oral squamous cell carcinoma

Yong-Le Qiu et al. Oncol Rep. 2019 Feb.

Abstract

Long non‑coding RNAs (lncRNAs) have been consistently demonstrated to be involved in oral squamous cell carcinoma (OSCC) as either tumor oncogenes or tumor suppressors. However, the underlying mechanisms of OSCC tumorigenesis and development have not yet been fully elucidated. The expression profiles of mRNAs and lncRNAs in OSCC were analyzed by a microarray assay. To verify the results of the microarray, 10 differentially expressed lncRNAs were randomly selected and measured by quantitative RT‑PCR (qRT‑PCR). Gene Ontology (GO) and metabolic pathway analyses were performed to analyze gene function and identify enriched pathways. Subsequently, two independent algorithms were used to predict the target genes of the lncRNAs. We identified 2,294 lncRNAs and 1,938 mRNAs that were differentially expressed in all three OSCC tissues by a microarray assay. Through the construction of co‑expression networks of differentially expressed genes, 4 critical lncRNAs nodes were identified as potential key factors in the pathogenesis of OSCC. Expression of the 4 critical lncRNA nodes was not associated with age, sex, smoking or tumor location (P>0.05) but was positively correlated with clinical stage, lymphatic metastasis, distant metastasis and survival status (P<0.05). Kaplan‑Meier analysis demonstrated that low expression levels of these 4 critical lncRNA nodes contributed to poor median progression‑free survival (PFS) and overall survival (OS) (P<0.05). GO and pathway analyses indicated that the functions and enriched pathways of many dysregulated genes are associated with cancer. Potential target genes of dysregulated lncRNAs were enriched in 43 metabolic pathways, with cancer pathways being the primary enrichment pathways. In summary, we analyzed the profile of lncRNAs in OSCC and identified the functions and enriched metabolic pathways of both dysregulated mRNAs and the target genes of dysregulated lncRNAs, providing new insights into molecular markers and therapeutic targets for OSCC.

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Figures

Figure 1.
Figure 1.
Volcano plot and hierarchical clustering analysis of differentially expressed (A and C) lncRNAs and (B and D) mRNAs between OSCC and paired adjacent normal tissues. The x-axis and y-axis in the volcano plot represent fold changes and P-values, respectively. The red dots to the right represent OSCC tissues, and the blue dots to the left represent paired adjacent normal tissues. For hierarchical clustering, black color represents 0, indicating that expression of these genes was not altered. Red color indicates that the expression level was increased. Green color indicates that the expression level was decreased. The color intensity indicates the degree of gene upregulation or downregulation. lncRNAs, long non-coding RNAs; OSCC, oral squamous cell carcinoma.
Figure 2.
Figure 2.
lncRNA-mRNA co-expression network. Genes directly interacting with (A) ENST00000583044, (B) NR_104048, (C) lnc-WRN-10:1 and (D) ENST00000527317. Each point in the network represents a gene. The point size represents the relationship coefficient of each gene. The line represents the relationship between genes. The circles represent mRNAs and the boxes represent lncRNAs. Red color represents gene upregulation, and green color represents gene downregulation. lncRNAs, long non-coding RNAs; mRNA, messenger RNA.
Figure 3.
Figure 3.
Top 30 GO enrichment terms using cis method. GO, Gene Ontology.
Figure 4.
Figure 4.
Top 30 GO enrichment terms using trans method. GO, Gene Ontology.
Figure 5.
Figure 5.
Top 30 KEGG enrichment terms using cis method. KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 6.
Figure 6.
Top 30 KEGG enrichment terms using trans method. KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 7.
Figure 7.
qRT-PCR validation of 10 differentially expressed lncRNAs. (A) Comparison of fold change [log2 (O/N)] of lncRNAs between the microarray and qRT-PCR results. (B) Normalized signal levels of lncRNAs in 72 pairs of OSCC and paired adjacent normal tissues. Data are presented as mean ± standard deviation (SD). lncRNAs, long non-coding RNAs; OSCC, oral squamous cell carcinoma. *P<0.05.
Figure 8.
Figure 8.
qRT-PCR validation of four critical node lncRNAs. Data are presented as mean ± standard deviation (SD). lncRNAs, long non-coding RNAs. *P<0.05.
Figure 9.
Figure 9.
The relationship of four critical node lncRNAs expression with OS in OSCC patients. (A) The relationship of ENST00000583044 expression with OS in OSCC patients; (B) the relationship of NR_104048 expression with OS in OSCC patients; (C) the relationship of lnc-WRN-10:1 expression with OS in OSCC patients; (D) the relationship of ENST00000527317 expression with OS in OSCC patients. lncRNAs, long non-coding RNAs; OS, overall survival; OSCC, oral squamous cell carcinoma.
Figure 10.
Figure 10.
The relationship of four critical node lncRNAs expression with PFS in OSCC patients. (A) The relationship of ENST00000583044 expression with PFS in OSCC patients; (B) the relationship of NR_104048 expression with PFS in OSCC patients; (C) the relationship of lnc-WRN-10:1 expression with PFS in OSCC patients; (D) the relationship of ENST00000527317 expression with PFS in OSCC patients. lncRNAs, long non-coding RNAs; OSCC, oral squamous cell carcinoma; PFS, progression-free survival.
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