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. 2020 Feb 28;40(2):BSR20194200.
doi: 10.1042/BSR20194200.

Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression

Hongxia Li  1 , Li Tong  1 , Hong Tao  1 , Zhe Liu  1
Affiliations

Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression

Hongxia Li et al. Biosci Rep. .

Abstract

Lung adenocarcinoma (LUAD) is a common type of lung cancer with high incidence and poor prognosis. Hypoxia and DNA methylation play important regulatory roles in cancer progression. The purpose of the present study was to explore the relationship between hypoxia and DNA methylation, and to identify key genes for hypoxia-regulated LUAD progression. Hypoxia score (HS) was calculated using the GSVA algorithm. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction (PPI) analysis were performed using clusterProfile package, STRING database and Cytoscape software. Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) were drawn using R software. Smoking status and cancer stages were significantly associated with LUAD hypoxia, and hypoxia is a poor prognostic factor for LUAD. Compared with HS-low group, 1803 aberrantly methylated DEGs were identified in HS-high group. KEGG analysis showed that the 1803 genes were enriched in the metabolic pathways associated with hypoxia stress, angiogenesis and cancer progression. FAM20C, MYLIP and COL7A1 were identified as the hypoxia-related key genes in LUAD progression, which were regulated by DNA methylation. Hypoxia in LUAD tumor cells led to changes in DNA methylation patterns. In-depth study of the relationship between hypoxia and DNA methylation is helpful to elucidate the mechanism of tumorigenesis, and provides new ideas for LUAD treatment.

Keywords: DNA methylation; Hypoxia; Hypoxia-related gene; Lung adenocarcinoma.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

All relevant data are contained within the paper. Additional information can be obtained by contacting Dr Zhe Liu (zheliu_lza@163.com).

Figures

Figure 1
Figure 1. Relationship between hypoxia and smoking, cancer stage and prognosis
(A) 533 LUAD patients were divided into two groups: hypoxia score (HS)-high group (n = 247) and HS-low group (n = 286), according to their HS values. One-way ANOVA analysis was performed to evaluate the differences of HS in different smoking states or different tumor stages. (B) HS of LUAD patients who reformed smoking, no-smoking and smoking. (C) HS of different cancer stages. (D) Analysis of overall survival (OS) based on HS. HS-high group, n = 245; HS-low group, n = 244. (E) Analysis of disease-free survival (DFS) based on HS. HS-high group, n = 228; HS-low group, n = 229.
Figure 2
Figure 2. Analysis of DMGs and DEGs in HS-high group compared with HS-low group
(A) Distribution of the DMPs with different genomic feature. (B) Heat map of DEGs between HS-high group and HS-low group. P < 0.05 and |log2 (fold change) |>2.0 were selected as the cutoff values.
Figure 3
Figure 3. Overlapping relationship between DEGs and DMGs
(A) Venn diagram of hypomethylation and up-regulated genes. (B) Venn diagram of hypermethylation and down-regulated genes.
Figure 4
Figure 4. GO term and KEGG pathway analysis for the aberrantly methylated DEGs
(A) The top 10 significant GO terms. (B) The top 10 significant KEGG pathways.
Figure 5
Figure 5. The top 2 significant modules in PPI network
Red nodes: up-regulated gene in HS-high group versus HS-low group; Green nodes: down-regulated gene in HS-high group versus HS-low group.
Figure 6
Figure 6. Survival analysis of UBE2D1, FAM20C, MYLIP and COL7A1 expression
(A–D) UBE2D1 (A), FAM20C (B), MYLIP (C) and COL7A1 (D) in TCGA database. (E–H) UBE2D1 (E), FAM20C (F), MYLIP (G) and COL7A1 (H) in Kaplan Meier-plotter database.
Figure 7
Figure 7. DNA methylation status of FAM20C, MYLIP and COL7A1 associated with overall survival
(A–C) Methylation probes of FAM20C. (D) Methylation probe of MYLIP. (E and F) Methylation probes of COL7A1.
Figure 8
Figure 8. Relative expression levels of FAM20C, MYLIP and COL7A1 in normoxic, hypoxic and hypoxic+Aza groups
*P < 0.05, hypoxic group versus normoxic group. #P < 0.05, hypoxic+Aza group versus hypoxic group.
Figure 9
Figure 9. FAM20C (A), MYLIP (B) and COL7A1 (C) potentially targeted by NF-κB
See this image and copyright information in PMC

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