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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (3) : 322-330     DOI: 10.1007/s11684-015-0408-9
RESEARCH ARTICLE |
TCGA whole-transcriptome sequencing data reveals significantly dysregulated genes and signaling pathways in hepatocellular carcinoma
Daniel Wai-Hung Ho,Alan Ka-Lun Kai,Irene Oi-Lin Ng()
Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China
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Abstract  

This study systematically evaluates the TCGA whole-transcriptome sequencing data of hepatocellular carcinoma (HCC) by comparing the global gene expression profiles between tumors and their corresponding non-tumorous liver tissue. Based on the differential gene expression analysis, we identified a number of novel dysregulated genes, in addition to those previously reported. Top-listing upregulated (CENPF and FOXM1) and downregulated (CLEC4G, CRHBP, and CLEC1B) genes were successfully validated using qPCR on our cohort of 65 pairs of human HCCs. Further examination for the mechanistic overview by subjecting significantly upregulated and downregulated genes to gene set enrichment analysis showed that different cellular pathways were involved. This study provides useful information on the transcriptomic landscape and molecular mechanism of hepatocarcinogenesis for development of new biomarkers and further in-depth characterization.

Keywords TCGA      whole-transcriptome sequencing      HCC      liver cancer     
Corresponding Authors: Irene Oi-Lin Ng   
Just Accepted Date: 14 July 2015   Online First Date: 17 August 2015    Issue Date: 26 August 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0408-9     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I3/322
Fig.1  Volcano plot of the WTS data. The color of the data points denotes the status of DGE and the intensity (light vs. dark) and shape (round dot vs. triangle) of the data points denote the average expression level of genes as defined by log2(CPM) (<1 vs.≥1).
Fig.2  Successful qPCR validation of top-listing DE genes.
Gene set # of genes # of DE genes P value FDR DE genes
GO biological process
MITOTIC_CELL_CYCLE 153 27 6.91E-33 5.70E-30 PRC1, PKMYT1, AURKA, CDKN2A, CDKN2C, CCNA2, CDCA5, MAD2L1, ZWINT, NEK2, ANLN, NDC80, PLK1, E2F1, KIF23, KIF2C, DLGAP5, CDC6, KIF11, UBE2C, BUB1B, NCAPH, BUB1, CENPF, BIRC5, CENPE, CDKN3
CELL_CYCLE_PROCESS 193 28 1.48E-31 6.09E-29 AURKA, CDCA5, CCNA2, MAD2L1, ZWINT, NEK2, NDC80, CDC6, NCAPH, BUB1, BIRC5, CDKN3, PRC1, PKMYT1, CDKN2A, CDKN2C, ANLN, PLK1, E2F1, KIF23, KIF2C, DLGAP5, KIF11, UBE2C, BUB1B, CENPF, CENPE, RACGAP1
CELL_CYCLE_GO_0007049 315 32 6.90E-31 1.90E-28 AURKA, CCNA2, CDCA5, MAD2L1, ZWINT, NEK2, NDC80, CDC20, CDT1, CDC6, NCAPH, CDC45, BUB1, BIRC5, CDKN3, PRC1, PKMYT1, CDKN2A, CDKN2C, ANLN, PLK1, E2F1, KIF23, KIF2C, DLGAP5, KIF11, MCM2, UBE2C, BUB1B, CENPF, CENPE, RACGAP1
CELL_CYCLE_PHASE 170 25 2.02E-28 4.17E-26 PKMYT1, AURKA, CDKN2A, CDKN2C, CDCA5, CCNA2, MAD2L1, ZWINT, NEK2, ANLN, NDC80, PLK1, E2F1, KIF2C, DLGAP5, CDC6, KIF11, UBE2C, BUB1B, NCAPH, BUB1, CENPF, BIRC5, CENPE, CDKN3
M_PHASE_OF_MITOTIC_CELL_CYCLE 85 19 1.49E-25 2.45E-23 PKMYT1, AURKA, KIF2C, DLGAP5, CDCA5, CCNA2, KIF11, UBE2C, MAD2L1, ZWINT, BUB1B, NEK2, ANLN, NCAPH, BUB1, BIRC5, NDC80, CENPE, PLK1
GO cellular component
NON_MEMBRANE_BOUND_ORGANELLE 631 29 2.11E-18 2.46E-16 CDCA5, ZWINT, KIF4A, NDC80, MAPT, CDK1, BUB1, CCNB2, PRC1, CDKN2A, ACTN2, ANLN, PLK1, KIF23, KIF2C, DLGAP5, KIF11, NEB, AURKA, MAD2L1, NEK2, CDC20, CDT1, TOP2A, BIRC5, MCM2, BUB1B, CENPF, CENPE
INTRACELLULAR_NON_MEMBRANE_BOUND_ORGANELLE 631 29 2.11E-18 2.46E-16 CDCA5, ZWINT, KIF4A, NDC80, MAPT, CDK1, BUB1, CCNB2, PRC1, CDKN2A, ACTN2, ANLN, PLK1, KIF23, KIF2C, DLGAP5, KIF11, NEB, AURKA, MAD2L1, NEK2, CDC20, CDT1, TOP2A, BIRC5, MCM2, BUB1B, CENPF, CENPE
MICROTUBULE_CYTOSKELETON 152 17 1.36E-17 1.05E-15 PRC1, AURKA, KIF4A, NEK2, CDC20, PLK1, KIF23, KIF2C, DLGAP5, MAPT, TOP2A, KIF11, CDK1, BUB1, CENPF, BIRC5, CCNB2
SPINDLE 39 11 1.51E-16 8.81E-15 KIF23, KIF4A, PRC1, AURKA, DLGAP5, BUB1, KIF11, CDK1, CENPF, BIRC5, CDC20
CYTOSKELETAL_PART 235 18 1.29E-15 6.03E-14 AURKA, KIF4A, NEK2, CDC20, MAPT, TOP2A, CDK1, BUB1, BIRC5, PRC1, ACTN2, ANLN, PLK1, KIF23, KIF2C, DLGAP5, KIF11, CENPF
GO molecular function
MICROTUBULE_MOTOR_ACTIVITY 16 5 1.96E-08 7.77E-06 KIF23, KIF4A, KIF11, CENPE, KIF2C
MOTOR_ACTIVITY 28 5 4.19E-07 8.29E-05 KIF23, KIF4A, KIF2C, KIF11, CENPE
CYTOSKELETAL_PROTEIN_BINDING 159 7 2.97E-05 0.004 NRCAM, ACTN2, ANLN, MAPT, BIRC5, RACGAP1, MAPK8IP2
CARBOHYDRATE_BINDING 72 5 4.90E-05 0.005 REG3A, CD34, MDK, THBS4, LPL
PROTEIN_KINASE_REGULATOR_ACTIVITY 39 4 6.21E-05 0.005 SFN,CDKN2A,CDKN2C,MAPK8IP2
KEGG pathway
KEGG_CELL_CYCLE 128 19 6.25E-22 1.16E-19 CDC45, PLK1, CCNA2, BUB1, MCM2, PTTG1, CDC6, CDC20, CCNB1, CCNE1, SFN, E2F1, CDK1, BUB1B, MAD2L1, CDKN2A, CDKN2C, PKMYT1, CCNB2
KEGG_OOCYTE_MEIOSIS 114 11 4.06E-11 3.78E-09 PLK1, BUB1, PTTG1, CDC20, CCNB1, CCNE1, CDK1, MAD2L1, AURKA, PKMYT1, CCNB2
KEGG_PROGESTERONE_MEDIATED_OOCYTE_MATURATION 86 8 2.62E-08 1.63E-06 CDK1, MAD2L1, PLK1, CCNA2, BUB1, PKMYT1, CCNB2, CCNB1
KEGG_P53_SIGNALING_PATHWAY 69 7 1.09E-07 5.06E-06 SFN, CDK1, CDKN2A, RRM2, CCNB2, CCNB1, CCNE1
KEGG_TIGHT_JUNCTION 134 4 0.006 0.226 MYH4, ACTN2, CTNNA2, PPP2R2C
Tab.1  Table 1 Summary of gene set enrichment analysis on significantly upregulated genes
Gene set # of genes # of DE genes P value FDR DE genes
GO biological process
SIGNAL_TRANSDUCTION 1634 70 9.98E-19 8.24E-16 DIRAS3, IGF1, IGF2, HPGD, GNA14, MARCO, CCL3, ADRA2B, TBXA2R, ADRA1B, ADRA1A, WNK2, IL1RL1, NR1I2, CXCL6, GRIA3, FCGR2B, GABRB3, CAMK2B, BCL2L10, AVPR1A, TRPV4, CCL19, NPY1R, APOA1, NR4A3, ESR1, CHRNA4, LILRB5, PDGFRA, ECM1, TNFRSF11B, GADD45G, GADD45B, CLEC1B, IL18R1, SOCS2, SOCS3, PTH1R, CTNND2, PTPRD, CRHBP, LIFR, CEACAM6, FPR1, CXCL12, NR4A1, CXCL14, SKAP1, WISP2, MCC, RND2, TACSTD2, EPHA2, NTRK2, TGFA, CHL1, LY6E, VIPR1, CD79A, IGFBP1, PRKAR2B, RET, RCAN1, ANXA3, SFRP5, SFRP1, GCGR, IGFALS, DTX1
RESPONSE_TO_EXTERNAL_STIMULUS 312 25 5.02E-13 2.07E-10 S100A8, SERPINE1, F9, SAA1, IL1RAP, TRPV4, CXCL2, FPR1, CXCL6, GCGR, CCL21, LECT2, CCL19, CD1D, ORM1, SELE, CXCL12, PGLYRP2, CCL3, ALB, LYVE1, CXCL14, CXCL13, FOS, MBL2
CARBOXYLIC_ACID_METABOLIC_PROCESS 178 19 2.13E-12 5.38E-10 SLC7A8, BBOX1, ASPA, GGT5, CYP39A1, ACOT12, GSTZ1, SLC3A1, SDS, HAO2, AKR1D1, SLC27A5, GLS2, FTCD, IGF1, CYP4A11, GLYAT, GCK, HPGD
ORGANIC_ACID_METABOLIC_PROCESS 180 19 2.61E-12 5.38E-10 SLC7A8, BBOX1, ASPA, GGT5, CYP39A1, ACOT12, GSTZ1, SLC3A1, SDS, HAO2, AKR1D1, SLC27A5, GLS2, FTCD, IGF1, CYP4A11, GLYAT, GCK, HPGD
LIPID_METABOLIC_PROCESS 325 24 8.36E-12 1.38E-09 CYP3A4, ALDH8A1, LCAT, APOF, PITPNM3, NR1I2, CYP39A1, CETP, THRSP, HAO2, SLC27A5, HPGD, APOA4, APOA1, BCO2, ACOT12, NPC1L1, IP6K3, AKR1D1, CYP4A11, GLYAT, RDH16, UGT2B7, SMPD3
GO cellular component
MEMBRANE 1994 90 1.23E-25 2.87E-23 IL1RAP, GHR, SLC22A1, CFTR, SLC3A1, C8A, GNA14, MARCO, ADRA2B, LYVE1, TBXA2R, ADRA1B, ADRA1A, TREH, CA9, CD4, GPR128, ABCB11, STEAP4, CD163, GRIA3, CD1D, SLC16A4, GABRB3, NAPSB, CNGA1, PLEKHB1, PTPRS, AVPR1A, UNC93A, TRPV4, SELP, NPY1R, SELE, SLC34A2, NCAM1, CNTFR, MRC1, HS3ST3A1, MAN1C1, SLCO1B3, CHRNA4, CLEC4M, PDGFRA, HS3ST3B1, CLEC1B, IL18R1, PKHD1, PTH1R, RHBG, CR1, PTPRD, LIFR, SRPX, CEACAM6, C7, C9, FPR1, STAB2, SLC13A2, CLDN2, PRSS8, GGT5, EPCAM, TACSTD2, MME, EPHA2, NTRK2, CHL1, LY6E, PROM1, VIPR1, FXYD1, ITGB8, ITGA9, CD79A, SLC5A1, NGFR, PITPNM3, CDHR2, SLC7A8, KCND3, B3GAT1, SIGLEC7, VSIG2,CLDN10, GCGR, SLC6A2, BASP1, SLC10A1
PLASMA_MEMBRANE 1426 75 2.65E-25 3.09E-23 LIFR, IL1RAP, CEACAM6, SLC22A1, GHR, CFTR, SLC3A1, C9, FPR1, STAB2, GNA14, MARCO, ADRA2B, LYVE1, ADRA1B, TBXA2R, SLC13A2, ADRA1A, TREH, CLDN2, PRSS8, CD4, ABCB11, EPCAM, TACSTD2, MME, EPHA2,NTRK2, STEAP4, CD163, LY6E, GRIA3, CD1D, PROM1, SLC16A4, GABRB3, VIPR1, CNGA1, FXYD1, ITGB8, ITGA9, CD79A, SLC5A1, NGFR, PTPRS, AVPR1A, UNC93A, TRPV4, SELP, NPY1R, SELE, SLC7A8, KCND3, SLC34A2, NCAM1, MRC1, SIGLEC7, SLCO1B3, CHRNA4, CLEC4M, VSIG2, PDGFRA, HS3ST3B1, CLEC1B, CLDN10, GCGR, IL18R1, SLC6A2, BASP1, PKHD1, PTH1R, RHBG, CR1, PTPRD, SLC10A1
INTRINSIC_TO_MEMBRANE 1348 72 1.09E-24 8.46E-23 LIFR, IL1RAP, CEACAM6, SLC22A1, GHR, SLC3A1, C8A, C7, C9, FPR1, STAB2, MARCO, ADRA2B, LYVE1, TBXA2R, ADRA1B, ADRA1A, SLC13A2, TREH, CA9, GPR128, ABCB11, GGT5, TACSTD2, MME, EPHA2, NTRK2, CD163, CHL1, LY6E, CD1D, PROM1, SLC16A4, GABRB3, VIPR1, CNGA1, FXYD1, ITGB8, ITGA9, SLC5A1, PLEKHB1, NGFR, PTPRS, PITPNM3, CDHR2, AVPR1A, SELP, NPY1R, SLC7A8, KCND3, SLC34A2, NCAM1, MRC1, B3GAT1, SIGLEC7, HS3ST3A1, MAN1C1, SLCO1B3, CHRNA4, CLEC4M, VSIG2, PDGFRA, HS3ST3B1, CLEC1B, GCGR, SLC6A2, PKHD1, PTH1R, RHBG, CR1, PTPRD, SLC10A1
INTEGRAL_TO_MEMBRANE 1330 70 1.21E-23 7.03E-22 LIFR, IL1RAP, CEACAM6, GHR, SLC22A1, SLC3A1, C8A, C7, C9, FPR1, STAB2, MARCO, ADRA2B, LYVE1, ADRA1B, TBXA2R, ADRA1A, SLC13A2, CA9, GPR128, ABCB11, GGT5, TACSTD2, MME, EPHA2, NTRK2, CD163, CHL1, LY6E, CD1D, PROM1, SLC16A4, GABRB3, VIPR1, CNGA1, FXYD1, ITGB8, ITGA9, SLC5A1, PLEKHB1, NGFR, PTPRS, PITPNM3, CDHR2, AVPR1A, SELP, NPY1R, SLC7A8, KCND3, SLC34A2, NCAM1, MRC1, B3GAT1, SIGLEC7, HS3ST3A1, MAN1C1, SLCO1B3, CHRNA4, CLEC4M, VSIG2, PDGFRA, HS3ST3B1, CLEC1B, GCGR, SLC6A2, PTH1R, RHBG, CR1, PTPRD, SLC10A1
MEMBRANE_PART 1670 78 4.27E-23 1.99E-21 IL1RAP, SLC22A1, GHR, CFTR, SLC3A1, C8A, GNA14, MARCO, ADRA2B, LYVE1, TBXA2R, ADRA1B, ADRA1A, TREH, CA9, GPR128, ABCB11, CD163, CD1D, SLC16A4, GABRB3, CNGA1, PLEKHB1, PTPRS, AVPR1A, SELP, NPY1R, SLC34A2, NCAM1, CNTFR, MRC1, HS3ST3A1, MAN1C1, SLCO1B3, CHRNA4, CLEC4M, PDGFRA, HS3ST3B1, CLEC1B, PKHD1, PTH1R, RHBG, CR1, PTPRD, LIFR, CEACAM6, C7, C9, FPR1, STAB2, SLC13A2, CLDN2, GGT5, TACSTD2, MME, EPHA2, NTRK2, CHL1, LY6E, PROM1, VIPR1, FXYD1, ITGB8, ITGA9, CD79A, SLC5A1, NGFR, PITPNM3, CDHR2, SLC7A8, KCND3, B3GAT1, SIGLEC7, VSIG2, CLDN10, GCGR, SLC6A2, SLC10A1
GO molecular function
OXYGEN_BINDING 22 12 9.98E-18 3.95E-15 CYP3A4, CYP3A7, CYP1A1, CYP2C19, CYP26A1, CYP1A2, CYP2E1, ALB, CYP2A6, CYP2A7, CYP8B1, HBB
RECEPTOR_ACTIVITY 583 34 3.28E-13 6.50E-11 LIFR, PTPRS, AVPR1A, IL13RA2, GHR, FPR1, STAB2, HPGD, MARCO, PGLYRP2, RET, CNTFR, ADRA2B, GABRP, MRC1, NR4A3, ADRA1B, TBXA2R, ADRA1A, SIGLEC7, MCC, CD4, GPR128, CHRNA4, LILRB5, TACSTD2, PDGFRA, TNFRSF11B, CLEC1B, GCGR, GABRB3, VIPR1, PTH1R, PTPRD
OXIDOREDUCTASE_ACTIVITY 289 24 6.83E-13 9.02E-11 CYP3A4, ALDH8A1, BBOX1, CYP26A1, CYP1A2, GPD1, CYP8B1, CYP39A1, GSTZ1, HAO2, PHGDH, HPGD, ADH1B, AKR7A3, KMO, BCO2, TDO2, SRD5A2, ACADL, CYP2A6, ADH6, ADH4, CYP4A11, RDH16
TRANSMEMBRANE_RECEPTOR_ACTIVITY 418 25 2.78E-10 2.75E-08 LIFR, PTPRS, AVPR1A, IL13RA2, GHR, FPR1, STAB2, HPGD, CNTFR, ADRA2B, GABRP, ADRA1B, TBXA2R, ADRA1A, CD4, GPR128, CHRNA4, LILRB5, PDGFRA, CLEC1B, GCGR, GABRB3, VIPR1, PTH1R, PTPRD
RECEPTOR_BINDING 377 23 9.87E-10 7.82E-08 APOF, PITPNM3 ,IL1RN, TNFRSF11B, SAA1, TGFA, CXCL2, CXCL6, CCL21, CCL19, IGF1, IGF2, CXCL12, APOA1, SOCS2, CCL3, ANGPTL1, CXCL14, CXCL13, MBL2, ADAMTS13, TNXB, DTX1
KEGG pathway
KEGG_RETINOL_METABOLISM 64 25 6.92E-31 1.29E-28 CYP4A11, CYP3A4, ADH1B, ADH1C, ADH4, ADH1A, CYP26A1, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2A13, UGT1A4, CYP3A7, LRAT, CYP2A6, CYP2A7, CYP4A22, CYP1A1, CYP1A2, ADH6, UGT2A1, CYP3A43, RDH16, UGT2B7
KEGG_DRUG_METABOLISM_CYTOCHROME_P450 72 23 4.00E-26 3.72E-24 CYP2E1, CYP3A4,GSTZ1, ADH1B, ADH1C, ADH4, ADH1A, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2A13, UGT1A4, CYP3A7, GSTM5, GSTA2, CYP2A6, CYP2A7, CYP1A2, ADH6, UGT2A1, CYP3A43, UGT2B7
KEGG_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 70 21 2.63E-23 1.63E-21 CYP2E1, CYP3A4, GSTZ1, ADH1B, ADH1C, ADH4, ADH1A, CYP2C9, CYP2C19, CYP2C8, CYP2B6, UGT1A4, CYP3A7, GSTM5, GSTA2, CYP1A1, CYP1A2, ADH6, UGT2A1, CYP3A43, UGT2B7
KEGG_DRUG_METABOLISM_OTHER_ENZYMES 51 12 1.75E-12 8.13E-11 CYP3A4, UPP2, CDA, CYP2A13, UGT1A4, CYP3A7, CYP2A6, CYP2A7, UGT2A1, CYP3A43, NAT2, UGT2B7
KEGG_LINOLEIC_ACID_METABOLISM 29 9 6.96E-11 2.59E-09 CYP2E1, CYP3A4, CYP1A2, PLA2G2A, CYP3A43, CYP2C9, CYP2C19, CYP2C8, CYP3A7
Tab.2  Summary of gene set enrichment analysis on significantly downregulated genes
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