Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data

Table 1 Summary of the most up and down-regulated genes from the meta-analysis of primary tumor samples from hepatocellular carcinoma patients, experimental log ratios indicating magnitude of change from control samples are shown

Top upregulated		Top downregulated
GPC3	2.426	CLEC4G	-4.212
ANLN	2.398	CLEC1B	-4.122
CCNB1	2.239	LINC01092	-3.834
ASPM	2.220	SLCO1B3	-3.788
CDK1	2.215	CLEC4M	-3.689
NEK2	2.121	HAMP	-3.657
EPS8L3	2.116	STAB2	-3.604
PBK	2.017	OIT3	-3.575
DTL	2.010	MT1M	-3.508
PRC1	1.993	HHIP	-3.417

GPC3: Glypican 3; ANLN: Anillin; CCNB1: Cycline B1; ASPM: Abnormal spindle-like microcephaly-associated protein; CDK1: Cyclin-dependent kinase 1; NEK2: NIMA related kinase 2; EPS8L3: Epidermal growth factor receptor kinase substrate 8-like protein 3; PBK: PDZ binding kinase; DTL: Denticleless E3 ubiquitin protein ligase homolog; PRC1: Protein regulator of cytokinesis 1; CLEC4G: C-type lectin domain family 4 member G; CLEC1B: C-type lectin domain family 1 member B; LINC01092: Long intergenic non-protein coding RNA 1092; SLCO1B3: Solute carrier organic anion transporter family member 1B3; CLEC4M: C-type lectin domain family 4 member M; HAMP: Hepcidin; STAB2: Stabilin 2; OIT3: Oncoprotein induced transcript 3; MT1M: Metallothionein 1M; HHIP: Hedgehog interacting protein.

Table 2 Top disease and functions identified by ingenuity pathway analysis network analysis

Top disease and function	P-score	Focus genes	Genes in network
Cell cycle; cellular assembly and organization; DNA replication, recombination and repair	46	33	BUB1, BUB1B, C4, C4BP, CENPA, CENPH, CENPK, CENPL, CENPM, CENPW, CNDP1, DSN1, ESR1, FCN2, FCN3, GGT5, HIST1H2BF, HJURP, HPS5, KNL1, LILRB5, MASP1, MASP2, MBL2, MND1, MPC1, NDC80, NUF2, OIP5, OVOS2, SLC1A4, TENM1, TUFT1, WHRN, XK
Cancer; cell death and survival; organismal injury and abnormalities	42	31	ANKS6, Ap1, AURKA, B9D1, BCKDHB, BOLA2/BOLA2B, CA5A, CBX5, CCT3, CDK1, CDKN2A, CEMIP, EPB41L5, estrogenreceptor, ETFRF1, EZH2, H2AFX, HIST1H2AM, HMGA1, KIF11, MCM2, MFAP4, MKI67, NAT2, NGFR, NT5DC2, PRKDC, Rnr, SETDB1, Smad2/3, TCF19, TK1, TMEM131L, TUBE1, ZSWIM5
Cancer; cell cycle; cellular movement	42	31	ATAD2, ATPase, BMP, BMP5, CCBE1, CEP55, CTH, DTL, ECT2, GORASP2, IGF2BP1, IL12 (family), IL18R1, IL1RAP, IPO9, KIF14, KIF23, LUM, MAP1LC3, MSH2, NAAA, NUP62, OLA1, PBLD, PLSCR4, RAD54B, SIGLEC1, STAU2, TEX37, TRAF5, TRIP13, VSIG2, VWA8, WDYHV1, XPO5
Cell morphology, cellular assembly and organization, DNA replication, recombination, and repair	39	30	ACAA2, ARMC6, BCHE, C4BPA, CDCA3, CDCA8, CENPE, CENPF, Ciap, CRNDE, ENO3, Enolase, FOXM1, KALRN, KIF20A, KIF2C, KIF4A, LRAT, MAGEA3/MAGEA6, MZT1, NAV1, NEB, PRC1, RAS, RASGRP2, RASSF4, SESTD1, SGO2, SRD5A1, SRD5A2, Steroid 5 alpha-Reductase, TARBP1, TGM3, transglutaminase, TRIO
Cancer; organismal injury and abnormalities; reproductive system disease	39	30	ANGPTL6, BMPER, Cysteine Protease, DPF3, EGLN, FNIP2, GCDH, GDF2, Granzyme B-Perforin-SRGN, GREM2, HMGCL, HOXA13, KIF15, LYVE1, MS4A7, MT1G, NOSTRIN, PCDH9, PDE7B, PLVAP, RNF125, RNF165, RRAGD, SERPINB9, SESN3, SLC7A2, Smad1/5/8, SPARCL1, SRGN, STC1, TPX2, TRIM16, Vegf, VSIG4, ZFP
Cancer, gastrointestinal disease, hepatic system disease	37	29	AKR1D1, ALDH, ALDH1A3, ALDH6A1, ALDH8A1, ANK3, CA2, COBLL1, CYP39A1, ENAH, ESM1, FOS, GBA, GLS2, GPM6A, GPSM2, GRHPR, GUCY1A1, HIST1H3H, histone-lysine N-methyltransferase, HOOK1, MECOM, NCKAP1L, NSD2, PALM2, PXMP2, Rab11, RAB11FIP4, sGC, SLC1A1, SMYD3, Sos, TSKU, UXS1

P-score indicates statistical significance [p-score = -log10(P value)] and the number of focus genes indicates the number of genes in our analysis that are a part of the respective network. Genes that are labeled red are upregulated in our analysis and genes that are green are downregulated. Genes in black are a part of the network but were not featured in our results. For P values and experimental log ratios of genes see Supplementary Table 1. TENM1: Teneurin transmembrane protein 1; GGT5: Gamma-glutamyltransferase5; SLC1A4: Solute carrier family 1 member 4; OVOS2: Alpha-2-macroglobulin like 1 pseudogene; XK: X-linked Kx blood group; WHRN: Whirlin; MPC1: Mitochondrial pyruvate carrier 1; LILRB5: Leukocyte immunoglobulin like receptor B5; CNDP1: Carnosine dipeptidase 1; CENPM: Centromere protein M; CENPL: Centromere protein L; ESR1: Estrogen receptor 1; C4BP: C4b-binding protein; TUFT1: Tuftelin 1; DSN1: MIND kinetochore complex component; KNL1: Kinetochore scaffold 1; BUB1: Mitotic checkpoint serine/threonine-protein kinase BUB1; HPS5: Hermansky-Pudlak syndrome 5 protien; FCN3: Ficolin 3; MASP1: MBL associated serine protease 1; MBL2: Mannose binding lectin 2; HIST1H2BF: Histone H2B type 1; OIP5: Opa interacting protein 5; NDC80: Kinetochore protein NDC80; BUB1B: BUB1 mitotic checkpoint serine/threonine kinase B; MND1: Meiotic nuclear divisions 1; CENPW: Centromere protein W; CENPH: Centromere protein H; CENPK: Centromere protein K; CENPA: Centromere protein A; ANKS6: Ankyrin repeat and SAM domain-containing protein 6; Ap1: Activator protein 1; AURKA: Aurora A kinase; B9D1: B9 domain containing 1; BCKDHB: 2-Oxoisovalerate dehydrogenase subunit beta; BOLA2/BOLA2B: BolA family member 2; CA5A: Carbonic anhydrase 5A; CBX5: Chromobox protein homolog 5; CCT3: Chaperonin containing TCP1 complex; CDK1: Cyclin-dependent kinase 1; CDKN2A: Cyclin dependent kinase inhibitor 2A; CEMIP: Cementum protein 1; EPB41L5: Erythrocyte membrane protein band 4.1 like 5; ETFRF1: Electron transfer flavoprotein regulatory factor 1; EZH2: Enhancer of zeste 2 polycomb repressive complex 2 subunit; H2AFX: H2A histone family, member X; HIST1H2AM: Histone cluster 1, H2am; HMGA1: High mobility group AT-hook 1; KIF11: Kinesin family member 11; MCM2: Mini-chromosome maintenance complex component 2; MFAP4: Microfibril associated protein 4; MKI67: Marker of proliferation Ki-67; NAT2: N-acetyltransferase 2; NGFR: Nerve growth factor receptor; NT5DC2: 5’-nucleotidase domain containing 2; PRKDC: Protein kinase, DNA-activated, catalytic subunit; Rnr: Ribonucleotide reductase; SETDB1: SET domain bifurcated histone lysine methyltransferase 1; Smad2/3: SMAD family member 2/3; TCF19: Transcription factor 19; TK1: Thymidine kinase 1; TMEM131L: Transmembrane 131 like; TUBE1: Tubulin epsilon 1; ZSWIM5: Zinc finger SWIM-type containing 5; ATAD2: ATPase family AAA domain containing 2; BMP: Bone morphogenetic protein; BMP5: Bone morphogenetic protein 5; CCBE1: Collagen and calcium binding EGF domains 1; CEP55: Centrosomal protein 55; CTH: Cystathionine gamma-lyase; DTL: Denticleless E3 ubiquitin protein ligase homolog; ECT2: Epithelial cell transforming 2; GORASP2: Golgi reassembly stacking protein 2; IGF2BP1: Insulin like growth factor 2 mRNA binding protein 1; IL12 (family): Interleukin-12; IL18R1: Interleukin-18 receptor 1; IL1RAP: Interleukin-1 receptor accessory protein; IPO9: Importin 9; KIF14: Kinesin-like protein 14; KIF23: Kinesin-like protein 23; LUM: Lumican; MAP1LC3: Microtubule-associated protein 1 light chain 3 beta; MSH2: MutS homolog 3; NAAA: N-acylethanolamine acid amidase; NUP62: Nucleoporin 62; OLA1: Obg like ATPase 1; PBLD: Phenazine biosynthesis like protein domain containing; PLSCR4: Phospholipid scramblase 4; RAD54B: RAD 54 homolog B; SIGLEC1: Sialic acid binding Ig like lectin 1; STAU2: Staufen double-stranded RNA binding protein 2; TEX37: Testis expressed 37; TRAF5: TNF receptor associated factor 5; TRIP13: Thyroid hormone receptor interactor 13; VSIG2: V-set and immunoglobulin domain containing 2; VWA8: Von Willebrand factor A domain containing 8; WDYHV1: WDYHV motif containing 1; XPO5: Exportin 5; ACAA2: Acetyl-CoA acyltransferase 2; ARMC6: Armadillo repeat containing 6; BCHE: Butyrylcholinesterase; C4BPA: Complement component 4 binding protein alpha; CDCA3: Cell division cycle associated 3; CDCA8: Cell division cycle associated 8; CENPE: Centromere protein E; CENPF: Centromere protein F; CRNDE: Colorectal neoplasia differentially expressed; ENO3: Enolase 3; FOXM1: Forkhead box M1; KALRN: Kalirin RhoGEF kinase; KIF20A: Kinesin family member 20A; KIF2C: Kinesin family member 2C; KIF4A: Kinesin family member 4A; LRAT: Lecithin-retinol acyltransferase; MAGEA3/MAGEA6: MAGE family member A3/A6; MZT1: Mitotic spindle organizing protein 1; NAV1: Neuron navigator 1; NEB: Nebulin; PRC1: Protein regulator of cytokinesis 1; RAS: RAS GTPase; RASGRP2: RAS guanyl releasing protein 2; RASSF4: Ras association domain family member 4; SESTD1: SEC14 and spectrin domain containing 1; SGO2: Shugoshin 2; SRD5A1: steroid 5 alpha-reductase 1; SRD5A2: Steroid 5 alpha-reductase 5; TARBP1: TAR RNA binding protein 1; TGM3: Transglutaminase 3; TRIO: Trio Rho guanine nucleotide exchange factor; ANGPTL6: Angiopoietin like 6; BMPER: BMP-binding endothelial regulator; DPF3: Double PHD fingers 3; EGLN: Endoglin; FNIP2: Folliculin interacting protein 2; GCDH: Glutaryl-CoA dehydrogenase; GDF2: Growth differentiation factor 2; GREM2: Gremlin 2; HMGCL: 3-hydroxy-3-methylglutaryl-CoA lyase; HOXA13: Homeobox A13; KIF15: Kinesin family member 15; LYVE1: Lymphatic vessel endothelial hyaluronan receptor 1; MS4A7: Membrane spanning 4-domains A7; MT1G: Metallothionein 1G; NOSTRIN: Nitric oxide synthase trafficking; PCDH9: Protocadherin 9; PDE7B: Phosphodiesterase 7B; PLVAP: Plasmalemma vesicle associated protein; RNF125: Ring finger protein 125; RNF165: Ring finger protein 165; RRAGD: Ras related GTP binding D; SERPINB9: Serpin family B member 9; SESN3: Sestrin 3; SLC7A2: Solute carrier family 7 member 2; Smad1/5/8: SMAD family member 1/5/8; SPARCL1: SPARC like 1; SRGN: Serglycin; STC1: Stanniocalcin; TPX2: TPX2 microtubule nucleation factor; TRIM16: Tripartite motif containing 16; Vegf: Vascular endothelial growth factor; VSIG4: V-set and immunoglobulin domain containing 4; ZFP: Zinc finger protein; AKR1D1: Aldo-keto reductase family 1 member D1; ALDH: Aldehyde dehydrogenase; ALDH1A3: Aldehyde dehydrogenase 1 family member A3; ALDH6A1: Aldehyde dehydrogenase 6 family member A1; ALDH8A1: Aldehyde dehydrogenase 8 family member A1; ANK3: Ankyrin 3; CA2: Carbonic anhydrase 2; COBLL1: Cordon-bleu WH2 repeat protein like 1; CYP39A1: Cytochrome P450 family 39 subfamily A member 1; ENAH: ENAH actin regulator; ESM1: Endothelial cell specific molecule 1; FOS: Fos proto-oncogene, AP-1 transcription factor subunit; GBA: Glucosylceramidase beta; GLS2: Glutaminase 2; GPM6A: Glycoprotein M6A; GPSM2: G protein signaling modulator 2; GRHPR: Glyoxylate and hydroxypyruvate reductase; GUCY1A1: Guanylate cyclase 1, soluble, alpha 1; HIST1H3H: Histone cluster 1 H3 family member h; histone-lysine N-methyltransferase; HOOK1: Hook microtubule tethering protein 1; MECOM: MDS1 and EVI1 complex locus; NCKAP1L: NCK associated protein 1 like; NSD2: Nuclear receptor binding SET domain protein 2; PALM2: Paralemmin 2; PXMP2: Peroxisomal membrane protein 2; Rab11: Rab 11 protein; RAB11FIP4: RAB11 family interacting protein 4; sGC: Soluble guanylyl cyclase; SLC1A1: Solute carrier family 1 member 1; SMYD3: SET and MYND domain containing 3; Sos: Son of Sevenless; TSKU: Tsukushi, small leucine rich proteoglycan; UXS1: UDP-glucuronate decarboxylase 1.