Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma

doi:10.3748/wjg.v24.i24.2605

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Jun 28, 2018; 24(24): 2605-2616
Published online Jun 28, 2018. doi: 10.3748/wjg.v24.i24.2605

Table 1 GO enrichment analysis of methylated-differentially expressed genes related with hepatocellular carcinoma

Category		Term	Count	%	P value
Hyper-LGs	GOTERM_BP_FAT	GO:0048545~response to steroid hormone stimulus	18	6.79	1.51E-08
	GOTERM_BP_FAT	GO:0009725~response to hormone stimulus	24	9.06	3.15E-08
	GOTERM_BP_FAT	GO:0007166~cell surface receptor linked signal transduction	60	22.64	1.75E-07
	GOTERM_BP_FAT	GO:0009719~response to endogenous stimulus	24	9.06	1.89E-07
	GOTERM_BP_FAT	GO:0007610~behavior	25	9.43	6.76E-07
	GOTERM_CC_FAT	GO:0044421~extracellular region part	48	18.11	1.97E-11
	GOTERM_CC_FAT	GO:0005886~plasma membrane	107	40.38	9.53E-10
	GOTERM_CC_FAT	GO:0005576~extracellular region	68	25.66	1.10E-08
	GOTERM_CC_FAT	GO:0044459~plasma membrane part	71	26.79	3.27E-08
	GOTERM_CC_FAT	GO:0031226~intrinsic to plasma membrane	47	17.74	1.22E-07
	GOTERM_MF_FAT	GO:0005539~glycosaminoglycan binding	11	4.15	7.78E-05
	GOTERM_MF_FAT	GO:0004714~transmembrane receptor protein tyrosine kinase activity	8	3.02	8.88E-05
	GOTERM_MF_FAT	GO:0001871~pattern binding	11	4.15	1.72E-04
	GOTERM_MF_FAT	GO:0030247~polysaccharide binding	11	4.15	1.72E-04
	GOTERM_MF_FAT	GO:0004713~protein tyrosine kinase activity	11	4.15	3.15E-04

Hypo-HGs	GOTERM_BP_FAT	GO:0006260~DNA replication	10	6.25	6.22E-05
	GOTERM_BP_FAT	GO:0051301~cell division	12	7.50	8.37E-05
	GOTERM_BP_FAT	GO:0051276~chromosome organization	15	9.38	1.41E-04
	GOTERM_BP_FAT	GO:0006259~DNA metabolic process	15	9.38	2.19E-04
	GOTERM_BP_FAT	GO:0007049~cell cycle	19	11.88	2.44E-04
	GOTERM_CC_FAT	GO:0005694~chromosome	14	8.75	3.77E-04
	GOTERM_CC_FAT	GO:0044427~chromosomal part	12	7.50	1.01E-03
	GOTERM_CC_FAT	GO:0000793~condensed chromosome	7	4.38	1.34E-03
	GOTERM_CC_FAT	GO:0000785~chromatin	8	5.00	2.77E-03
	GOTERM_CC_FAT	GO:0044421~extracellular region part	19	11.88	3.60E-03
	GOTERM_MF_FAT	GO:0030414~peptidase inhibitor activity	6	3.75	1.24E-02
	GOTERM_MF_FAT	GO:0016849~phosphorus-oxygen lyase activity	3	1.88	1.65E-02
	GOTERM_MF_FAT	GO:0009975~cyclase activity	3	1.88	1.80E-02
	GOTERM_MF_FAT	GO:0004857~enzyme inhibitor activity	7	4.38	3.53E-02
	GOTERM_MF_FAT	GO:0008092~cytoskeletal protein binding	10	6.25	3.83E-02

Top five terms were listed on the basis of P value if over five terms in the category, Hyper-LGs (hypermethylated, lowly expressed genes), Hypo-HGs (hypomethylated, highly expressed genes).

Table 2 KEGG pathway analysis of methylated-differentially expressed genes related with hepatocellular carcinoma

Category		Term	Count	%	P value	Gene
Hyper-LGs	KEGG_PATHWAY	hsa04610:Complement and coagulation cascades	7	2.64	6.62E-03	C7, CR1, CD55, THBD, MASP1, SERPINE1, PLAUR
	KEGG_PATHWAY	hsa05414:Dilated cardiomyopathy	7	2.64	2.50E-02	LAMA2, ITGA9, ADCY1, ADRB1, ITGB8, ADCY5, TGFB3
	KEGG_PATHWAY	hsa05200:Pathways in cancer	15	5.66	2.94E-02	FGFR2, PTGS2, FLT3, PIK3CD, FZD1, TGFB3, MMP2, WNT2, LAMA2, RAC2, NKX3-1, LAMC2, WNT11, HHIP, GSTP1
	KEGG_PATHWAY	hsa04310:Wnt signaling pathway	9	3.40	3.16E-02	WNT2, SFRP5, NKD2, RAC2, PRICKLE1, SFRP1, FZD1, WNT11, FOSL1
	KEGG_PATHWAY	hsa04062:Chemokine signaling pathway	10	3.77	3.97E-02	CXCL1, ADCY1, DOCK2, CCL23, RAC2, TIAM1, ADCY5, PIK3CD, CCL19, CXCL6
Hypo-HGs	KEGG_PATHWAY	hsa04110:Cell cycle	7	4.38	2.32E-03	CCNE2, E2F2, PRKDC, CDC20, MCM2, SFN, PTTG1
	KEGG_PATHWAY	hsa00140:Steroid hormone biosynthesis	3	1.88	9.07E-02	CYP17A1, CYP7A1, UGT2B11

Top five terms were listed on the basis of P value if over five terms in the category, Hyper-LGs (hypermethylated, lowly expressed genes), Hypo-HGs (hypomethylated, highly expressed genes).

Table 3 Hub genes for hypermethylated, lowly expressed genes ranked in cytoHubba

Catelogy	Rank methods in cytoHubba
Catelogy	MNC	Degree	EPC	Closeness	Radiality	Stress
Gene symbol top 10	*PTGS2*	ADCY5	*PTGS2*	*PIK3CD*	*PIK3CD*	*PTGS2*
	*PIK3CD*	*MMP2*	*PIK3CD*	*PTGS2*	*PTGS2*	*PIK3CD*
	ADCY5	*PTGS2*	*MMP2*	*MMP2*	*MMP2*	*MMP2*
	ADCY1	*PIK3CD*	ADCY5	*ESR1*	*ESR1*	PRKG1
	*CXCL1*	PRKG1	ADCY1	PRKG1	TLR2	*ESR1*
	*ESR1*	ADCY1	*ESR1*	TLR2	SERPINE1	FYN
	*MMP2*	*ESR1*	*CXCL1*	FYN	PRKG1	RAC2
	FYN	FYN	TLR2	*CXCL1*	SNAI1	SERPINE1
	TLR2	*CXCL1*	CALCA	SERPINE1	CRP	*CXCL1*
	SERPINE1	TLR2	PTGER2	ADCY5	*CXCL1*	ADCY5

Bold gene symbols were the overlap hub genes in top 10 by six ranked methods respectively in cytoHubba. MNC: Maximum neighborhood component; Degree: Node connect degree; EPC: Edge percolated component.

Table 4 Hub genes for hypomethylated, highly expressed genes ranked in cytoHubba

Catelogy	Rank methods in cytoHubba
Catelogy	MCC	MNC	Degree	EPC	Closeness	Radiality
Gene symbol top 10	*CDC45*	*CDC45*	*CDC45*	*CDC45*	*CDKN3*	*CDKN3*
	*DTL*	*AURKB*	*AURKB*	*AURKB*	*CDC45*	PRKDC
	RACGAP1	*DTL*	*CDKN3*	*CDKN3*	*AURKB*	*CDC45*
	*AURKB*	RACGAP1	*DTL*	*DTL*	PTTG1	PTTG1
	CDC20	CDC20	RACGAP1	RACGAP1	*DTL*	*MCM10*
	*CDKN3*	*CDKN3*	CDC20	CDC20	*MCM2*	BRCA1
	RRM2	*MCM2*	*MCM2*	*MCM2*	*MCM10*	PI3
	*MCM2*	PTTG1	PTTG1	PTTG1	RACGAP1	*AURKB*
	*MCM10*	RRM2	RRM2	RRM2	CDC20	*MCM2*
	MKI67	*MCM10*	*MCM10*	*MCM10*	RRM2	*DTL*

Bold gene symbols were the overlap hub genes in top 10 by six ranked methods respectively in cytoHubba. MCC: Maximal cilque centrality; MNC: Maximum neighborhood component; Degree: Node connect degree; EPC: Edge percolated component.

Table 5 Modules analysis of the protein–protein interaction network

Category	Module	Score	Nodes	Enrichment and pathway description	Genes
Hyper-LGs	1	10.00	10	GO.0005886: plasma membrane	ADRB1, VIPR1, PTGDR, SCTR, CALCA, GPR83, ADCY1, ADCY5, PTGER2, PTGER4
				GO.0007187: G-protein coupled receptor signaling pathway
				GO.0004016: adenylate cyclase activity
				has04080: Neuroactive ligand-receptor interaction
	2	6.00	6	GO.0051953: negative regulation of amine transport	CCL19, ADRA2B, P2RY12, CXCL6, NPY5R, CXCL1
				GO.0008009: chemokine activity
				has04062: Chemokine signaling pathway
	3	5.68	20	GO.0005886: plasma membrane	OXT, SERPINE1, EDNRB, PTGS2, ADRA1A, IL18, CRP, SOCS3, EFNB3, MMP2, EPHB1, TIAM1, EFNA5, TBXA2R, EPHA2, TLR2, SNAI1, FYN, GNA14, PROK2
				GO.0005003: ephrin receptor activity
				GO.0051240: positive regulation of multicellular organismal process
				hsa04360: Axon guidance
	4	4.50	5	GO.0005605: basal lamina	ITGA9, ITGB8, COL6A2, LAMC2, LAMA2
				GO.0030198: extracellular matrix organization
				hsa04512: ECM-receptor interaction
Hypo-HGs	1	17.56	19	GO.0022402: cell cycle process	CDCA5, KIF14, BRCA1, CENPF, RACGAP1, NEK2, CDKN3, DTL, MCM2, MCM10, CDC45, PTTG1, ANLN, CDC20, RRM2, AURKB, MKI67, STIL, CCNE2
				GO.0015630: microtubule cytoskeleton
				GO.0003688: DNA replication origin binding
				hsa04110: Cell cycle
	2	5.00	5	GO.0007188: adenylate cyclase-modulating G-protein coupled receptor signaling pathway	CNR1, CCL20, ADCY6, HTR1D, CCL25
	2	5.00	5	hsa04062: Chemokine signaling pathway	CNR1, CCL20, ADCY6, HTR1D, CCL25
	3	4.50	5	GO.0005615: extracellular space	REN, PLA2G1B, TIMP1, MMP9, VWF

Hyper-LGs: Hypermethylated, lowly expressed genes; Hypo-HGs: Hypomethylated, highly expressed genes.

Citation: Sang L, Wang XM, Xu DY, Zhao WJ. Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma. World J Gastroenterol 2018; 24(24): 2605-2616
URL: https://www.wjgnet.com/1007-9327/full/v24/i24/2605.htm
DOI: https://dx.doi.org/10.3748/wjg.v24.i24.2605