Journal of Prevention and Treatment for Stomatological Diseases ›› 2021, Vol. 29 ›› Issue (10): 677-683.doi: 10.12016/j.issn.2096-1456.2021.10.005

• Basic Study • Previous Articles     Next Articles

Significance of phosphoinositol metabolism by DNA methylation may contribute in oral leukoplakia carcinogenesis

WANG Guangchao(),LIU Lijun,JIANG Weiwen()   

  1. Department of Oral Mucosal Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
  • Received:2021-01-30 Revised:2021-05-01 Online:2021-10-20 Published:2021-06-23
  • Contact: Weiwen JIANG E-mail:wgc119@foxmail.com;wwjiang33@hotmail.com
  • Supported by:
    National Natural Science Foundation of China(81671036)

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Abstract:

Objective To study the role of DNA methylation in oral leukoplakia carcinogenesis. Methods DNA methylation was detected in forty cases of oral squamous cell carcinoma (OSCC), twenty-eight cases of oral leukoplakia (OLK) and forty cases of healthy oral mucosa. Download the expression profile data of OSCC, OLK and healthy oral mucosa from Gene Expression Omnibus (GEO) database. DNA methylation data and expression profile data were compared for repeatability, DNA methylation data for difference analysis and corresponding expression profile data for IPA pathway analysis. Results The data analysis showed that DNA methylation had greater flexibility and instability. Ingenuity Pathway Analysis (IPA) analysis showed that genes related to OLK differential methylation sites were mainly concentrated in the process of cell movement and differentiation. Genes related to differential methylation sites of OSCC are mainly enriched in cell proliferation, migration, oxidation regulation, and anti-apoptosis processes. The genes associated with OLK and OSCC differential methylation sites are co-enriched in phosphoinositol metabolism and phospholipase C signaling pathway. Conclusion DNA methylation is involved in the formation of oral squamous cell carcinoma, and the activation of phosphoinositol metabolism may promote oral leukinoma.

Key words: oral leukoplakia, oral squamous cell carcinoma, epigenetics, DNA methylation, inositol, phosphoinositol, metabolism, phospholipase C, inflammation, calcium signal

CLC Number: 

  • R78

Figure 1

Heatmap of partial detection of Illumina 450K methylation chip Each column represents a sample, and each row represents a DNA methylation site. Only the clustering results of the first twenty loci were shown"

Table 1

External expression profile data set selected for this experiment"

Data set profile Region Type Sample type and sample size
GSE33205 BALTIMORE（USA） HUEX-1_0-ST HNSCC（n=50） vs. Normal（n=25）
GSE85195 NAVI MUMBAI（INDIA） AGILENT-014850 OLK（n=15） vs. OSCC（n=34） vs. Normal（n=1）

Table 2

5% overlap of DNA methylation spectrum at the lowest β value"

DNA methylation（5%） OSCC OLK Normal
OSCC 0.62 0.61 0.65
OLK 0.61 0.62 0.66
Normal 0.65 0.66 0.67

Table 3

The 5% overlap rate of the expression profile at the maximum expression level"

Expression（5%） OSCC OLK Normal
OSCC 0.80 0.75 0.80
OLK 0.75 0.83 0.82
Normal 0.80 0.82 0.80

Figure 2

The genes associated with OLK differential DNA methylation sites are mainly involved in cell movement and differentiation This figure shows the major interaction networks of differential DNA methylation sites in OLK tissues. Among them, the changes of DNA methylation status and expression amount of COL18A1, EBF2, IGF1R and KLF4 were supported by data. The activation/suppression of other genes were predicted by IPA internal algorithm. The COL18A1 promoter region is hypopethylated, and the gene host region is hypermethylated, with reduced expression. The EBF2 promoter region is hypomethylated and its expression is elevated. The main body region of IGF1R gene was hypomethylated and its expression was increased. Both KLF4 host region and promoter region were hypopethylated and their expression was increased. COL18A1: collagen type XVIII alpha 1 chain; EBF2: EBF transcription factor 2; IGF1R: insulin-like growth factor 1 receptor; KLF4: Kruppel like factor 4; OLK: oral leukoplakia"

Figure 3

OSCC differential DNA methylation related gene enrichment network OSCC: oral squamous cell carcinoma"

Table 4

The first six pathways with significant enrichment of genes related to different methylation sites of OSCC and OLK"

Canonical pathways OSCC vs. Normal OLK vs. Normal
Superpathway of inositol phosphate compounds 2.837 2.324
3-phosphoinositide Biosynthesis 2.828 2.309
D-myo-inositol (1, 4, 5, 6)-tetrakisphosphate biosynthesis 2.673 2.111
D-myo-inositol (3, 4, 5, 6)-tetrakisphosphate biosynthesis 2.673 2.111
D-myo-inositol-5-phosphate metabolism 2.324 2.309
Phospholipase C signaling -0.943 3.128
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