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Home , CLEC4M, Dipeptidase 1, Urocanase

Supplementary Table S1. Clinicopathological characteristics of HCC patients

Discovery Set 1 Discovery Set 2 Validation Set 1 Validation Set 2 Total no. of patients 10 10 20 44 Age, years Mean (SD) 66.1 (5.9) 68 (8.9) 61.3 (10.9) 64.8 (9.9) Sex, no. of patients (%) Male 10 9 16 (80) 35 (79.5) Female 0 1 4 (20) 9 (20.5) Hepatitis virus infection, no. of patients (%) No 1 1 2 (10) 9 (20.5) B 2 5 7 (35) 12 (27.3) C 6 3 11 (55) 20 (45.5) B+C 1 1 0 3 (6.8) Background liver, no. of patients (%) Normal 0 0 1 (5) 5 (11.4) Chronic hepatitis (CH) 7 3 8 (40) 23 (52.3) Liver cirrhosis (LC) 2 4 8 (40) 8 (18.2) CH + LC 0 0 1 (5) 0 Precirrhosis 1 3 2 (10) 8 (18.2) Tumor size, cm3 mean (SD) 68.3 (42.0) 120.9 (218.1) 87.8 (111.9) 176.4 (256.7) Histology, no. of patients (%) Well 1 0 1 (5) 5 (11.4) Well to moderately 0 0 4 (20) 0 Moderately 5 10 8 (40) 27 (61.4) Moderately to poorly 1 0 1 (5) 0 Poorly 3 0 6 (30) 12 (27.3) Intrahepatic metastases, no. of patients (%) 0 7 7 17 (85) 30 (68.2) 1 1 1 2 (10) 14 (31.8) 2 2 2 0 0 3 0 0 1 (5) 0 Portal vein involvement, no. of patients (%) 0 4 1 10 (50) 17 (38.6) 1 5 8 7 (35) 24 (54.5) 2 0 1 0 1 (2.3) 3 1 0 3 (15) 2 (4.5) Supplementary Table S2. List of up-regulated in HCC (Discovery Set 1)

Transcript Fold RefSeq symbol P-value Gene description Cluster ID change 2337716 NM_006252 PRKAA2 6.71E-04 4.42 kinase, AMP-activated, alpha 2 catalytic subunit 2379863 NM_016343 CENPF|TUBD1|P 1.05E-04 3.22 Centromere protein F, 350/400ka (mitosin) | tubulin, delta AK1 1 | p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast) 2427007 NM_002959 SORT1|PSRC1|M 1.24E-04 3.14 Sortilin 1 | /-rich coiled-coil 1 | myosin YBPHL binding protein H-like 2441386 NM_003617 RGS5|UPK1B 5.06E-06 3.27 Regulator of G-protein signalling 5 | uroplakin 1B 2449559 NM_018136 ASPM 4.37E-05 3.03 Asp (abnormal spindle) homolog, microcephaly associated (Drosophila) 2469252 NM_001034 RRM2 6.68E-06 3.36 Ribonucleotide reductase M2 polypeptide 2544201 NM_004881|NM_147 TP53I3|PFN4 7.69E-06 3.67 Tumor protein p53 inducible protein 3 | profilin family, 184 member 4 2784113 NM_001237 CCNA2 4.01E-04 3.43 Cyclin A2 2813414 NM_031966 CCNB1 5.02E-06 3.53 Cyclin B1 2899102 NM_003531 HIST1H3C 5.21E-05 4.94 Histone cluster 1, H3c 2946215 NM_003537 HIST1H3B 3.73E-06 4.99 Histone cluster 1, H3b 2947077 NM_003533 HIST1H3I 2.49E-05 3.61 Histone cluster 1, H3i 2997376 NM_018685 ANLN 1.43E-05 3.39 Anillin, actin binding protein 3025433 NM_020299 AKR1B10|LOC34 4.50E-04 18.03 Aldo-keto reductase family 1, member B10 (aldose 0888|LOC441282 reductase) | similar to aldo-keto reductase family 1, member B10 3260586 NM_005063 SCD|LOC645313| 8.76E-05 3.43 Stearoyl-CoA desaturase (delta-9-desaturase) | similar to LOC651109 Acyl-CoA desaturase (Stearoyl-CoA desaturase) (Fatty acid desaturase) (Delta(9)-desaturase) 3329343 NM_002391|NM_001 MDK 4.38E-04 3.90 Midkine (neurite growth-promoting factor 2) 012334|NM_0010123 33 3375545 NM_013402 FADS1|FADS3 2.74E-04 3.34 Fatty acid desaturase 1 | fatty acid desaturase 3 3590388 NM_018454|NM_016 NUSAP1 1.62E-05 3.09 Nucleolar and spindle associated protein 1 359 3756193 NM_001067 TOP2A 7.29E-06 4.63 Topoisomerase (DNA) II alpha 170kDa 3881443 NM_012112 TPX2|TINAGL1 2.10E-06 3.11 TPX2, microtubule-associated, homolog (Xenopus laevis) | tubulointerstitial nephritis antigen-like 1

3639031 NM_199414|NM_199 PRC1 8.32E-06 3.17 Protein regulator of cytokinesis 1 413|NM_003981 Supplementary Table S3. List of genes down-regulated in HCC (Discovery Set 1)

Transcript Fold RefSeq Gene symbol P-value Gene description Cluster ID change 2331679 NM_032793 MFSD2|LOC731362 1.37E-05 3.98 Major facilitator superfamily domain containing 2 | similar to ribosomal protein S2 2337786 NM_000562 C8A 6.13E-04 3.77 Complement component 8, alpha polypeptide 2377332 NM_000651|NM_000 CR1|LOC653907 3.69E-08 3.32 Complement component (3b/4b) 1 (Knops blood 573 group) | similar to complement component (3b/4b) receptor 1 isoform F precursor 2388085 NM_003679 KMO 2.13E-04 3.96 Kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) 2403080 NM_003665|NM_173 MAP3K6|FCN3 4.00E-09 18.47 Mitogen-activated protein kinase kinase kinase 6 | ficolin 452 (collagen/fibrinogen domain containing) 3 (Hakata antigen) 2439138 NM_005894 CD5L 1.52E-06 12.18 CD5 molecule-like 2443120 NM_001937 DPT 4.15E-07 5.63 Dermatopontin 2475911 NM_014600 EHD3 3.24E-09 3.30 EH-domain containing 3 2502686 NM_006770 MARCO 8.19E-10 6.79 Macrophage receptor with collagenous structure 2547231 NM_000348 SRD5A2 7.70E-05 4.20 Steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2) 2678298 NM_004944 DNASE1L3|ACTB 5.72E-07 9.65 Deoxyribonuclease I-like 3 | actin, beta 2693620 NM_144639 UROC1 2.30E-06 6.38 Urocanase domain containing 1 2716124 NM_001528 HGFAC 9.54E-07 4.84 HGF activator 2729852 NM_005953 MT2A|MT1M|LOC4 1.53E-04 3.38 Metallothionein 2A | metallothionein 1M | hypothetical 41019|NUTF2 gene supported by X97260; BC070289 | nuclear transport factor 2 2745899 NM_022475 HHIP 7.34E-08 3.97 Hedgehog interacting protein 2772566 NM_144646 IGJ 4.02E-04 7.76 Immunoglobulin J polypeptide, linker protein for immunoglobulin alpha and mu polypeptides 2773434 NM_002089 CXCL2 1.94E-05 5.90 Chemokine (C-X-C motif) 2 2775259 NM_152545 RASGEF1B|ALK|R 6.25E-05 3.25 RasGEF domain family, member 1B | anaplastic BM41 lymphoma kinase (Ki-1) | RNA binding motif protein 41 2775390 MOP-1 8.90E-04 3.53 2775909 NM_016619 PLAC8 7.54E-11 13.74 Placenta-specific 8 2792127 NM_000909 NPY1R|LOC729743| 6.08E-09 3.06 Neuropeptide Y receptor Y1 | similar to neuropeptide Y LOC731120 receptor Y1 2794584 NM_005277|NM_201 GPM6A|MPDU1 9.68E-09 3.47 M6A | mannose-P-dolichol utilization defect 591|NM_201592 1 2807716 NM_000587 C7 2.60E-05 11.43 Complement component 7 2816536 NM_001882 CRHBP 3.45E-09 13.85 Corticotropin releasing hormone binding protein 2842624 NM_017675 PCLKC 6.73E-04 4.88 Protocadherin LKC 2853055 NM_031900 AGXT2 4.55E-04 3.61 -glyoxylate aminotransferase 2 2854092 NM_002310 LIFR 2.95E-07 7.18 Leukemia inhibitory factor receptor alpha 2854409 NM_001737 C9|ASTN2 7.35E-05 16.46 Complement component 9 | astrotactin 2 2876608 NM_004887 CXCL14 8.13E-08 4.89 Chemokine (C-X-C motif) ligand 14 2883283 NM_138379 TIMD4 3.38E-08 4.36 T-cell immunoglobulin and mucin domain containing 4 2907513 NM_018960 GNMT 1.61E-04 6.98 N-methyltransferase 2955761 NM_016593 CYP39A1 6.59E-04 3.97 Cytochrome P450, family 39, subfamily A, polypeptide 1 2975257 NM_022568|NM_170 ALDH8A1|HBS1L 7.13E-04 3.41 Aldehyde dehydrogenase 8 family, member A1 | 771 HBS1-like (S. cerevisiae) 2982630 NM_024492|NM_145 LPAL2|LOC732058| 5.06E-05 3.86 Lipoprotein, Lp(a)-like 2 | similar to Apolipoprotein(a) 727 PLGLB2 precursor (Apo(a)) (Lp(a)) | plasminogen-like B2 2982730 NM_005577 LPA|LOC732390|L 8.05E-06 7.98 Llipoprotein, Lp(a) | similar to Apolipoprotein(a) OC732436|PLGLB2| precursor (Apo(a)) (Lp(a)) | plasminogen-like B2 | TMEM166 transmembrane protein 166 2995476 INMT 1.51E-05 3.47 Indolethylamine N-methyltransferase 3049292 NM_001013398|NM_ IGFBP3 4.56E-05 4.96 Insulin-like growth factor binding protein 3 000598 3058944 NM_001010932|NM_ HGF 1.38E-05 5.69 Hepatocyte growth factor (hepapoietin A; scatter factor) 000601|NM_0010109 31|NM_001010933|N M_001010934 3060332 NM_024636 STEAP4 5.41E-06 3.70 STEAP family member 4 3065740 NM_173054|NM_005 RELN 3.74E-04 5.62 045 3095257 NM_194294 INDOL1 2.39E-04 3.08 Indoleamine-pyrrole 2,3 dioxygenase-like 1 3095313 NM_020130 C8orf4 1.82E-07 3.76 8 open reading frame 4 3113133 NM_006438 COLEC10 1.37E-06 13.60 Collectin sub-family member 10 (C-type lectin) 3128817 NM_000680|NM_033 ADRA1A 1.87E-04 3.71 Adrenergic, alpha-1A-, receptor 303|NM_033304|NM_ 033302 3193631 NM_004108|NM_015 FCN2 1.70E-07 3.64 Ficolin (collagen/fibrinogen domain containing lectin) 2 837 (hucolin) 3204285 NM_006274 CCL19 4.46E-05 11.65 Chemokine (C-C motif) ligand 19 3204301 NM_002989 CCL21 1.51E-04 4.04 Chemokine (C-C motif) ligand 21 3215570 NM_000507 FBP1 2.86E-04 3.65 Fructose-1,6-bisphosphatase 1 3237286 NM_001009567 MRC1 1.08E-06 4.72 , C type 1 3251566 NM_152635 OIT3|C1orf146 2.82E-08 10.95 Oncoprotein induced transcript 3 | chromosome 1 open reading frame 146 3286602 NM_000609|NM_199 CXCL12 3.57E-06 5.02 Chemokine (C-X-C motif) ligand 12 (stromal cell-derived 168|NM_001033886 factor 1) 3302533 NM_003015 SFRP5 1.38E-05 4.31 Secreted frizzled-related protein 5 3333811 NM_001039752 SLC22A10 3.50E-04 5.11 Solute carrier family 22 (organic anion/cation transporter), member 10 3348940 NM_031938|NM_001 KCTD9|BCDO2|LO 3.85E-05 4.40 Potassium channel tetramerisation domain containing 9 | 037290 C728291|LOC64251 beta-carotene dioxygenase 2 | similar to potassium 3|LOC728707|LOC7 channel tetramerisation domain containing 9 | 29404|LOC730942|L hypothetical protein LOC728707 OC650978|LOC6478 52|LOC731540 3349858 NM_006169 NNMT 2.28E-05 9.79 Nicotinamide N-methyltransferase 3359121 NR_003512|NM_0010 INS-IGF2 7.64E-04 13.10 Insulin- insulin-like growth factor 2 | insulin-like growth 07139|NM_000612 factor 2 (somatomedin A) 3360401 NM_000518 HBB 3.13E-06 3.35 Hemoglobin, beta 3362826 NM_006691 XLKD1 6.72E-09 8.65 Extracellular link domain containing 1 3365318 NM_006512 SAA4 9.90E-04 3.56 Serum amyloid A4, constitutive 3374934 NM_152852|NM_022 MS4A6A|LOC64368 2.47E-05 3.25 Membrane-spanning 4-domains, subfamily A, member 349|NM_152851 0 6A | hypothetical protein 3402786 NM_000616 CD4|S100PBP 1.43E-06 3.07 CD4 molecule | S100P binding protein 3426257 NM_003877 SOCS2 6.46E-04 4.70 Suppressor of cytokine signaling 2 3428573 NM_152323 SPIC|LOC646120 2.74E-05 3.06 Spi-C transcription factor (Spi-1/PU.1 related) | similar to Spi-C transcription factor (Spi-1/PU.1 related) 3429159 NM_017564 STAB2 3.97E-09 9.37 Stabilin 2 3442706 NM_004244|NM_203 CD163 9.19E-06 4.07 416 3443936 NM_016509 CLEC1B 1.47E-10 6.14 C-type lectin domain family 1, member B 3457794 NM_001638 APOF|STAT2 7.09E-04 10.21 Apolipoprotein F | signal transducer and activator of transcription 2, 113kDa 3457891 NM_013267 GLS2 9.06E-06 8.54 2 (liver, mitochondrial) 3465274 NM_001920|NM_133 DCN 2.73E-05 8.72 Decorin 503|NM_133504|NM_ 133505|NM_133506|N M_133507 3466687 NM_002108 HAL 8.59E-04 4.82 ammonia- 3468345 NM_000618 IGF1 9.19E-04 5.16 Insulin-like growth factor 1 (somatomedin C) 3472366 NM_006843 SDS 7.40E-05 11.63 Serine 3486096 NM_207361 FREM2 3.91E-04 4.61 FRAS1 related extracellular matrix protein 2 3502475 NM_003891 PROZ 7.77E-05 3.30 Protein Z, vitamin K-dependent plasma glycoprotein 3544525 NM_005252 FOS 5.63E-04 5.88 V-fos FBJ murine osteosarcoma viral oncogene homolog 3565524 NM_000161|NM_001 GCH1|LOC202181 2.98E-06 3.49 GTP cyclohydrolase 1 (dopa-responsive dystonia) | 024024|NM_0010240 hypothetical protein LOC202181 70|NM_001024071 3642664 NM_000517 HBA2|HBA1 2.14E-05 3.01 Hemoglobin, alpha 2 | hemoglobin, alpha 1 3651478 NM_005622|NM_202 ACSM3 2.19E-04 4.11 Acyl-CoA synthetase medium-chain family member 3 000 3661940 NM_020988|NM_138 GNAO1 2.93E-05 5.01 Guanine nucleotide binding protein (G protein), alpha 736 activating activity polypeptide O 3662139 NM_175617 MT1E|MT1M|MT1 6.83E-04 7.58 Metallothionein 1E (functional) | metallothionein 1M | A|NUTF2 metallothionein 1A (functional) | nuclear transport factor 2 3662150 NM_176870 MT1M|MT1JP|NUT 6.55E-04 6.69 Metallothionein 1M | metallothionein 1J (pseudogene) | F2 nuclear transport factor 2 3662158 C20orf127|MT1JP|N 5.85E-04 5.65 Chromosome 20 open reading frame 127 | metallothionein UTF2 1J (pseudogene) | nuclear transport factor 2 3662201 NM_005951|NM_005 MT1F|MT1H|LOC6 6.89E-04 6.17 Metallothionein 1F (functional) | metallothionein 1H | 949|NM_001039954 45745|LOC727730| metallothionein 1H-like protein | similar to MT1A|NUTF2 metallothionein 1H-like protein | metallothionein 1A (functional) | nuclear transport factor 2 3662247 NM_005952 MT1X|MT1A|NUTF 3.34E-04 4.93 Metallothionein 1X | metallothionein 1A (functional) | 2 nuclear transport factor 2 3662417 NM_000078 CETP 1.44E-07 6.67 Cholesteryl ester transfer protein, plasma 3667811 NM_001361 DHODH 5.29E-05 3.68 Dihydroorotate dehydrogenase 3692999 NM_005950 MT1G|NUTF2 8.51E-04 8.16 Metallothionein 1G | nuclear transport factor 2 3696035 NM_000229 LCAT 1.50E-05 3.98 Lecithin-cholesterol acyltransferase 3742627 UNQ5783 2.48E-07 3.26 DTFT5783 3748798 NM_002404 MFAP4 1.01E-05 4.91 Microfibrillar-associated protein 4 3768627 NM_007168 ABCA8 8.15E-04 3.23 ATP-binding cassette, sub-family A (ABC1), member 8 3793827 NM_032649 CNDP1 2.87E-05 4.19 Carnosine 1 (metallopeptidase M20 family) 3819130 NM_214677|NM_214 CLEC4M 8.20E-09 13.16 C-type lectin domain family 4, member M 678|NM_214679|NM_ 014257|NM_214676|N M_214675 3830306 NM_021175 HAMP 8.23E-09 52.87 Hepcidin antimicrobial peptide 3848525 NM_198492 CLEC4G 6.15E-10 6.21 C-type lectin superfamily 4, member G 3881391 NM_181353|NM_002 ID1 3.28E-06 6.01 Inhibitor of DNA binding 1, dominant negative 165 helix-loop-helix protein 3883233 C20orf127|MT1JP|M 6.22E-04 5.41 Chromosome 20 open reading frame 127 | metallothionein T1M|MT1A 1J (pseudogene) | metallothionein 1M | metallothionein 1A (functional) 3890640 NM_002591 PCK1 9.83E-04 7.09 Phosphoenolpyruvate carboxykinase 1 (soluble) 3974019 NM_004615 TSPAN7 6.45E-04 3.16 Tetraspanin 7 4007164 NM_002621 CFP 5.21E-10 3.72 Complement factor properdin 4011008 NM_007268 EIF4B|VSIG4|LOC6 5.70E-05 3.50 Eukaryotic translation initiation factor 4B | V-set and 43873|LOC339881|L immunoglobulin domain containing 4 | similar to OC645430|LOC3924 eukaryotic translation initiation factor 4B | hypothetical 85|LOC650271|THR LOC645430 | similar to ataxin 7-like 3 | hypothetical SP protein LOC650271 | thyroid hormone responsive (SPOT14 homolog, rat) 4020655 NM_014253 ODZ1 8.93E-04 3.60 Odz, odd Oz/ten-m homolog 1(Drosophila) 4027639 NM_000132|NM_019 F8 1.69E-05 3.01 Coagulation factor VIII, procoagulant component 863 (hemophilia A) Supplementary Table S4. List of siRNA

Gene symbol ID AKR1B10 43766 133050 112090 ANLN 132619 132620 132621 CCNB1 118838 118839 DEPDC1 148669 148670 148671 HCAP-G 125362 125363 125364 HIST1H3B 214117 214118 214119 HIST1H3C 13270 45052 44958 HIST1H3I 13272 44960 45054 RRM2 9302 110819 110822 TPX2 19774 136425 136426 Supplementary Table S5. List of TaqMan Assays

Gene symbol Assay ID AKR1B10 Hs00252524_m1 ANLN Hs00218803_m1 C7 Hs00175109_m1 CCNA2 Hs00153138_m1 COLEC10 Hs00197571_m1 CRHBP Hs00181810_m1 HAMP Hs00221783_m1 HCAP-G Hs00254617_m1 HIST1H3I Hs00605800_s1 RGS5 Hs00186212_m1 RRM2 Hs00357247_g1 TPX2 Hs00201616_m1 Supplementary Table S6. Effects of siRNA treatment on the growth of xenografts

Estimate* Standard error* t-Value Adjusted P-value Control (Intercept) 3.744 0.189 TPX2 -1.239 0.161 -7.699 < 0.001 RRM2 -1.153 0.168 -6.878 < 0.001 AKR -0.499 0.162 -3.088 0.012 HCAPG -0.782 0.168 -4.667 < 0.001 *On a natural logarithmic scale.