Supplementary Table S1 Demographic characteristics of HCC patients • Age (year; mean ± SD) 53.950 ± 11.802 • Gender (number; %) Male 79 (79%) Female 21 (21%) • AFP (ng/mL; mean ± SD) 23928.571 ± 79577.084 • Tumor encapsulation (number; %) Absent 61 (63.5%) Present 35 (36.5%) • by Edmondson grading I-II 46 (47.9%) III-IV 50 (52.1%) • Tumor microsatellite formation (number, %) Absent 45 (46.9%) Present 51 (53.1%) • Tumor size (cm; mean ± SD) Length 8.3 ± 5.0 Width 7.4 ± 4.3 • Venous invasion (number; %) Absent 42 (43.3%) Present 55 (56.7%) • Direct liver invasion (number; %) Absent 53 (60.2%) Present 35 (39.8%) • pTNM staging (number, %) I-II 37(38.1%) III-IV 60 (61.9%) • Hepatitis B surface antigen (number; %) Absent 22 (23.4%) Present 72 (76.6%) • Background liver disease (number; %) Normal 7 (7.2%) Chronic hepatitis 36 (37.1%) Cirrhosis 54 (55.7%)

Supplementary Table S2 Primer sequences used in qRT-PCR study

Genes Sequences Forward: cagatcatcggtcaggccaa NDUFA4 Reverse: tctgtcccaacaaacatctgga Forward: aaaagacatccggggatcat Human NDUFA4L2 Reverse: tccgggttgttctttctgtc Forward: ctcctccactgcccactcta Human NDUFA4L2 HRE-1 (ChIP) Reverse: gtcactctgtactctgcctt Forward: gagagcaggtccccagaga Human NDUFA4L2 HRE-2 (ChIP) Reverse: ctccttggcccagacttatg Forward: gaggatgaggtggaacgtgt Human 18S Reverse: agaagtgacgcagccctcta Forward: gcactcttccagccttcctt Human ACTB Reverse: aatgccagggtacatggtgg Forward: ctttgctgacctgctggatt Human HPRT Reverse: ctgcattgttttcggagtgt

Supplementary Table S3 The target regions of shRNA and siRNA constructs shRNA clones Genebank Target nucleotides shNDUFA4-30 NM_002489 124-144 shNDUFA4-88 NM_002489 353-373 shNDUFA4L2-90 NM_020142 60-80 shHIF-1α NM_181054 2,123-2,141 shHIF-2α NM_001430 1,992-2,012 siRNA clones Genebank Target nucleotides siNDUFA4L2-1 NM_020142 246-264 siNDUFA4L2-3 NM_020142 103-121 siNDUFA4L2-4 NM_020142 146-164

Supplementary Table S4 Clinico-pathological correlation of NDUFA4L2 over-expression in human HCC

Clinico-pathological features No. of Cases Mean P value • Tumor size

≤ 5 cm 34 1.516 0.195 > 5 cm 62 2.068 • Cellular differentiation by

Edmondson grading

I – II 46 2.011 0.411 III – IV 50 1.678 • Tumor encapsulation

Absent 61 2.203 *0.039 Present 35 1.346 • Tumor microsatellite formation

Absent 45 1.198 *0.002 Present 51 2.402 • Direct liver invasion

Absent 53 1.506 0.156 Present 35 2.106 • Hepatitis B surface antigen

Absent 22 1.937 0.635 Present 72 1.712 • Venous invasion

Absent 42 1.592 0.238 Present 55 2.074 *P<0.05; N=100

Supplementary Table S5 Down Regulated in NDUFA4L2 Knockdown HCC cells NTC (FPKM) shL2-90 (FPKM) Fold change SH3GL1P2 0.761623 0.380601 0.499723617 ADAM8 0.463544 0.231426 0.499253577 SCAMP1-AS1 1.67707 0.837189 0.49919741 SH3YL1 3.37804 1.68605 0.499120792 HIST1H3E 2.81929 1.40268 0.49752952 REREP3 0.647432 0.322092 0.497491628 NR3C2 0.142956 0.0711156 0.497464954 SEC31B 0.184359 0.0917107 0.497457135 MYO7B 0.375316 0.186703 0.497455478 TMEM254-AS1 0.108506 0.0537568 0.495426981 C21orf119 2.80135 1.38549 0.494579399 EXOC3L4 0.380068 0.187964 0.494553606 PRH1 1.68311 0.831699 0.494144174 KLF8 0.393827 0.194483 0.493828508 DENND2C 0.189965 0.0937807 0.493673571 MAGEC1 0.464209 0.229 0.49331228 C9orf173 0.311722 0.153522 0.492496519 CHSY3 0.30456 0.149903 0.492195298 MRC2 0.17374 0.0855132 0.49219063 RPEL1 0.799184 0.392808 0.491511342 UNC5B-AS1 6.78942 3.33296 0.490904967 KLF3-AS1 0.672482 0.329245 0.489596748 DNAAF3 0.30395 0.148685 0.489175851 LRRC39 0.304849 0.149007 0.488789532 AHRR 0.44304 0.216479 0.488621795 COL11A2 0.234426 0.1144 0.488000478 C1QL1 0.978865 0.476937 0.487234706 KCNMB4 0.856615 0.417361 0.487221214 NFATC1 0.206553 0.100588 0.48698397 NECAB1 0.157432 0.0765264 0.486091773 CCDC150 0.397478 0.193184 0.486024384 FAM160A1 1.31199 0.636949 0.485483121 FAM27E2 0.175755 0.0850939 0.484162044 LDLRAD4 0.17958 0.0867033 0.48281156 APOH 1.73112 0.835328 0.482536162 HSD11B2 1.04178 0.502687 0.482527021 LOC102723385 0.321261 0.154866 0.482056646 PTPN22 0.113555 0.0546526 0.481287482 GPR160 11.0757 5.28357 0.477041632 RXFP1 0.987013 0.467323 0.473471981 RHD 0.162375 0.0766867 0.472281447 SPDYE7P 0.346316 0.163499 0.472109287 ENO1-AS1 0.350972 0.16494 0.469952019 LINC01023 1.45134 0.681979 0.469896096 HIST1H3J 0.314392 0.147728 0.46988473 HIST1H2AH 0.311348 0.146297 0.469882575 LOC101059948 0.300673 0.141281 0.469882563 SPINK13 0.28554 0.134169 0.469878126 LINC00571 0.275742 0.129565 0.469877639 RBAKDN 0.236504 0.111127 0.46987366 LOC102723809 0.989734 0.465049 0.469872713 LINC00539 0.231392 0.108724 0.469869313 CHKB-AS1 0.209275 0.0983317 0.469868355 LOC102467147 0.596706 0.280372 0.469866232 CLLU1OS 0.187297 0.0880038 0.469862304 LOC728228 0.188766 0.0886939 0.469861628 LOC100288911 0.353943 0.166304 0.469860966 LOC101928043 0.183026 0.0859966 0.46986002 CSAG1 0.197675 0.0928795 0.469859618 LOC100507661 0.506705 0.238079 0.469857215 ATP6AP1L 0.657166 0.308774 0.469856931 LOC101927142 0.160727 0.0755185 0.469855718 RASSF1-AS1 0.313603 0.147348 0.469855199 KCNE2 0.152578 0.0716895 0.469854763 ORM1 0.144345 0.0678209 0.469852783 LINC00412 0.138731 0.0651828 0.469850286 CLEC3B 0.141587 0.0665246 0.469849633 LOC101927843 0.398402 0.187189 0.469849549 C1orf162 0.129236 0.0607214 0.469848958 TAS2R46 0.12702 0.0596802 0.469848843 LY6G6C 0.271594 0.127608 0.469848377 ACOT6 0.115725 0.0543729 0.469845755 LOC338694 0.117994 0.0554389 0.469845077 CALML6 0.103644 0.0486965 0.469843889 RAB41 0.107102 0.0503212 0.4698437 MTNR1A 0.2064 0.0969754 0.469842054 LINC00592 0.21858 0.102698 0.469841706 SUGT1P3 0.109789 0.0515834 0.469841241 C11orf42 0.495811 0.232952 0.469840322 IL6 0.666018 0.312922 0.469840154 MRGPRE 0.171333 0.0804984 0.469835934 LOC100630918 0.462935 0.217503 0.469834858 CACNA1G-AS1 0.152721 0.0717536 0.469834535 UBAP1L 0.159026 0.0747159 0.469834492 LOC101928708 0.150337 0.0706334 0.469833773 FLJ26850 0.152359 0.0715833 0.469833092 LYRM9 0.294243 0.138245 0.469832757 CHAD 0.252903 0.118822 0.469832307 SOWAHD 0.203721 0.0957147 0.469832271 FAM19A3 0.323458 0.151971 0.46983225 GPR162 0.143504 0.0674227 0.469831503 LOC344967 0.20047 0.0941871 0.469831396 LOC101927257 0.218851 0.102823 0.469831072 ALKBH3-AS1 0.109737 0.0515578 0.469830595 PCDHGA4 0.380018 0.178544 0.469830376 BIN3-IT1 0.462118 0.217117 0.469830217 OVCH1 0.118593 0.0557185 0.469829585 LOC643770 0.116508 0.0547389 0.46982954 SCOC-AS1 0.156577 0.0735644 0.469828902 ZNF77 0.206199 0.0968782 0.469828661 LOC100507501 1.50383 0.706542 0.469828372 DLX6 0.113088 0.0531319 0.469827922 STK4-AS1 0.148604 0.0698183 0.469827865 FAAH 0.350529 0.164688 0.469827033 LINC00501 0.152769 0.071775 0.469826994 CHRNA3 0.12244 0.0575255 0.469826037 C19orf57 0.342693 0.161006 0.469825762 LOC100128361 0.291304 0.136862 0.469825337 SLC16A9 0.151454 0.0711566 0.469823181 WNT4 0.128984 0.0605996 0.469822614 ROBO4 0.105102 0.0493792 0.469821697 GNN 0.110843 0.0520763 0.469820377 GPR133 0.110861 0.0520846 0.469818962 BEGAIN 0.269196 0.126472 0.469813816 PDC 0.189156 0.088868 0.469813276 TMOD2 0.194677 0.0914606 0.469806911 LOC100132529 0.190634 0.0895539 0.469768772 C4B_2 0.17881 0.083828 0.468810469 LOXL1 2.29853 1.07474 0.467577104 NEURL1B 14.8661 6.94447 0.467134622 LOC101927811 0.818921 0.382264 0.466789837 NBPF11 3.29108 1.52877 0.464519246 CDKN2B-AS1 1.11798 0.517799 0.46315587 PDE5A 0.875884 0.404448 0.461759776 SIRPB1 0.503763 0.232441 0.461409433 MRPL42P5 1.27122 0.58609 0.461045295 YPEL1 0.894964 0.412066 0.460427459 RORC 0.54904 0.252755 0.46035808 RAET1E-AS1 0.132074 0.0607946 0.460307101 SNHG21 1.88131 0.865421 0.46000978 OAZ1 264.986 121.621 0.458971417 ZNF773 0.513736 0.235754 0.45890107 GDPD3 1.0658 0.488542 0.458380559 OSCP1 0.601027 0.274812 0.457237362 FYN 1.11284 0.506793 0.45540509 ARMC12 0.102323 0.0465853 0.455276917 JAZF1 1.4475 0.65765 0.45433506 DRD4 1.09236 0.494223 0.45243601 GKAP1 0.776409 0.351116 0.452230719 HOXC5 0.10029 0.0452748 0.451438827 UCN 2.49897 1.12314 0.44944117 LINC00854 1.39452 0.626722 0.449417721 USP27X-AS1 0.522854 0.23497 0.449398876 PRODH 51.7476 23.2366 0.44903725 GUSBP3 0.476315 0.213876 0.449022181 AGER 1.24434 0.558654 0.448956073 ANKRD16 2.48992 1.11587 0.448154961 TMEM200B 0.307683 0.137875 0.448107305 LINC00035 3.35578 1.50175 0.447511458 NAPSA 0.414363 0.185412 0.447462732 PCDHGB6 0.220671 0.09874 0.447453449 MOB3B 0.159164 0.0712172 0.447445402 RYR2 0.18139 0.0810289 0.446710954 SULT2B1 0.578977 0.257859 0.445370023 MARCH1 0.350718 0.1561 0.445086936 C7orf63 0.193633 0.0861464 0.44489524 GPR161 1.77598 0.789736 0.444676179 FGF13 0.979771 0.434695 0.44367 IQUB 0.147545 0.065389 0.443180047 SLAIN1 0.430705 0.190134 0.441448323 LOC100289580 0.203496 0.0896847 0.440719719 ZMYND15 0.684168 0.30139 0.440520457 PLXNC1 0.221024 0.0972151 0.439839565 CYP4V2 1.27494 0.55906 0.438499067 RFESD 0.28061 0.122854 0.437810484 INHA 1.64436 0.718676 0.437055146 CA11 2.9746 1.29828 0.436455322 AKAP7 2.91843 1.26941 0.434963319 STAM-AS1 0.508268 0.220428 0.433684592 ID4 0.168992 0.0732889 0.43368266 ELFN1 0.175335 0.0760397 0.433682379 CLCNKB 0.156194 0.067579 0.432660666 TP73 0.716315 0.309883 0.432607163 PCDHGC5 0.175796 0.0758945 0.431719152 SOX2-OT 0.128938 0.055615 0.431331338 ENDOU 0.13769 0.0593478 0.431024766 LOC101929696 0.19855 0.0855091 0.430667842 KCNQ1 0.851664 0.366275 0.43006984 TSC22D1-AS1 0.21402 0.0918467 0.429150079 C6orf201 0.236836 0.101233 0.427439241 DFNB59 0.391718 0.167311 0.427121041 TMLHE-AS1 0.173076 0.0739239 0.427118145 TMLHE-AS1 0.173076 0.0739239 0.427118145 EFCAB6 0.120402 0.051424 0.42710254 TNFRSF10C 0.258494 0.110062 0.425781643 MAP6D1 0.489804 0.207111 0.422844648 HIST1H2BF 1.67682 0.700388 0.417688243 TMEM255B 1.0088 0.421313 0.417637787 SEPSECS-AS1 0.457054 0.190882 0.417635553 RDH12 0.254 0.106077 0.417625984 CFI 0.217863 0.0909851 0.417625297 GCNT7 0.229032 0.0956494 0.417624611 GRIN3B 0.140605 0.0587195 0.417620284 LINC00672 0.24622 0.102826 0.41761839 LOC100506127 0.167125 0.0697942 0.417616754 SLC25A30 0.516657 0.215446 0.41700006 LEPREL2 0.761054 0.316827 0.416300289 MEF2BNB-MEF2B 0.999973 0.416123 0.416134236 SLC46A1 0.133671 0.0554205 0.414603766 CACNA1I 0.168339 0.0697818 0.414531392 C8orf88 1.1889 0.492802 0.414502481 FRMPD2P1 0.278034 0.114698 0.41253228 CAHM 1.07877 0.443501 0.411117291 SCN4B 0.897833 0.36868 0.410633158 LRRC48 0.408808 0.16721 0.409018415 CSTA 1.69038 0.690632 0.408566121 OCLM 1.55509 0.635353 0.408563492 CHRD 0.330678 0.135096 0.408542449 CARD16 0.985751 0.402297 0.408112191 DYX1C1 0.173436 0.0705666 0.406874005 HTN3 4.3861 1.7824 0.406374684 FAM177B 5.9514 2.4105 0.405030749 ESRRG 0.204072 0.0824918 0.4042289 ACAP1 1.03057 0.416404 0.404052126 LOC102723344 0.326557 0.131511 0.402719893 EDN2 0.314667 0.126722 0.402717794 CD72 0.489856 0.197272 0.402714267 SP5 0.189877 0.0764653 0.402709649 LOC100507091 0.166932 0.0672249 0.402708288 ADAM21 0.135249 0.0544658 0.402707599 TAS1R1 0.128495 0.0517458 0.40270672 EYA4-AS1 0.119859 0.048268 0.402706513 LINC01301 0.101735 0.040969 0.402703101 ABCA9 0.109987 0.044292 0.402702138 NELL2 2.60453 1.04411 0.400882309 CD27-AS1 0.712814 0.284163 0.398649578 HELB 0.92407 0.368369 0.398637549 STRC 0.148696 0.0592755 0.398635471 LOC100652758 1.24799 0.496146 0.39755607 GK3P 0.444083 0.175699 0.395644508 KHK 0.205561 0.0806824 0.392498577 TMEM163 0.67143 0.262881 0.391524061 TPRG1 0.165795 0.0649119 0.391519045 BCO2 0.238751 0.0934723 0.391505376 CNTNAP2 0.549875 0.214121 0.389399409 MINOS1-NBL1 1.95244 0.760246 0.389382516 TRIM46 0.331079 0.128665 0.388623259 C3orf35 0.532672 0.206917 0.388451054 RAB42 0.576116 0.223454 0.387862861 RPL21P44 0.507752 0.196459 0.386919205 MMP17 0.366065 0.141636 0.386914892 SLC2A5 0.259613 0.0998334 0.384546999 FAM218A 0.529097 0.203387 0.384403994 IQCH-AS1 0.82053 0.312688 0.381080521 PNMT 0.183747 0.0694839 0.378149847 TMEM231 0.169 0.0639 0.378106509 SLC46A3 0.136616 0.0516466 0.378042103 RIPPLY1 0.220583 0.0831552 0.376979187 WWOX 1.60014 0.60293 0.37679828 HOXC-AS2 0.724577 0.272371 0.375903458 LOC101926944 0.675825 0.254043 0.375900566 SCGB1B2P 0.559666 0.210376 0.375895623 LOC102724050 0.462842 0.173977 0.375888532 LOC389247 0.395221 0.148557 0.375883367 C1QTNF5 0.202459 0.0760981 0.375869188 MIOX 0.190298 0.0715267 0.375866798 LOC644762 0.166942 0.0627479 0.375866469 C2orf66 0.115518 0.0434189 0.375862636 KRT83 0.14136 0.0531319 0.375862337 KEL 0.101365 0.0380992 0.375861491 DCAF13P3 0.106288 0.0399494 0.375859928 PCDHA8 0.105914 0.0398088 0.37585966 ELN 0.13279 0.0499103 0.375858875 CFP 0.33763 0.1269 0.375855226 TMEM71 0.13547 0.0509162 0.375848527 BDNF-AS 0.708116 0.265093 0.374363805 FAM47E 0.211108 0.0786016 0.372328855 PCDHGA9 0.207984 0.0770573 0.370496288 MIR31HG 0.682256 0.251855 0.36915029 LMO7-AS1 0.510594 0.188145 0.368482591 FLJ37035 0.284851 0.104881 0.368196004 F10 0.811843 0.298511 0.367695478 KLHL38 1.18774 0.43554 0.366696415 LOC541473 0.943829 0.344718 0.365233533 LOC101929690 1.70882 0.623387 0.364805538 HCG8 0.904578 0.329031 0.363739777 IL36G 0.669362 0.241916 0.361412808 KLHDC1 0.248485 0.0898034 0.361403706 LOC100289495 0.33509 0.121102 0.361401415 PRSS12 0.14223 0.0514019 0.361399845 KLHL32 0.152303 0.0547998 0.359807752 ASTN2 0.540104 0.193101 0.357525588 ZNRD1-AS1 0.394484 0.140256 0.355542937 PLCXD3 1.85172 0.65771 0.355188689 PLA2G3 0.962212 0.340172 0.353531238 C9orf9 4.22403 1.48853 0.352395698 RGS1 0.312885 0.110253 0.352375473 LINC00330 0.206753 0.0728537 0.352370703 MX2 0.138111 0.048666 0.352368747 SEPT4 0.255911 0.0901723 0.352358046 SPEF2 0.139176 0.0485178 0.348607519 TMPRSS4 0.683955 0.237738 0.347593043 PTPRN 0.347346 0.120397 0.346619797 DHX58 0.374161 0.12953 0.346187871 PADI2 0.126378 0.0431819 0.341688427 ICA1L 0.334447 0.113401 0.339070167 GSTM2 0.327509 0.109912 0.335599938 SIGLEC9 0.435997 0.146318 0.335594052 RTBDN 0.141812 0.0474779 0.334794658 LEF1 0.437049 0.146182 0.334475082 ELAVL4 0.481143 0.159537 0.331579177 RPL36A 4.44968 1.47201 0.330812553 LOC101928158 0.849408 0.279267 0.328778396 CDK20 0.203425 0.0667248 0.328006882 ANKRD23 0.859082 0.281594 0.327784775 SGK3 0.42708 0.138482 0.324253067 CD27 0.274625 0.0879717 0.32033391 C1QTNF3-AMACR 0.405598 0.128939 0.31789851 FHIT 0.314659 0.0997069 0.316872869 SEMA3B-AS1 1.72601 0.5408 0.313323793 PHGR1 0.548371 0.171785 0.313264195 LINC01251 0.459606 0.143974 0.313255266 LOC606724 0.18093 0.0566761 0.31324877 LOC606724 0.18093 0.0566761 0.31324877 C2orf70 0.276113 0.0864898 0.313240594 IGFL1 0.241898 0.0757714 0.313236984 LOC100507006 0.237523 0.0744009 0.313236613 ZRANB2-AS2 0.472714 0.148071 0.31323591 HSPB2 0.647612 0.202855 0.313235394 EPN2-IT1 0.220821 0.0691688 0.313234701 CGB7 0.203983 0.0638942 0.313232965 SMIM24 0.196225 0.0614638 0.31323124 RAET1G 0.205959 0.064512 0.31322739 TMEM240 0.152835 0.0478721 0.313227337 GJC3 0.152997 0.0479228 0.313227057 KRTAP5-9 0.142156 0.0445271 0.313227018 TMIGD1 0.140361 0.0439646 0.313225184 ARID3C 0.135363 0.0423991 0.31322518 ARGFXP2 0.139953 0.0438368 0.313225154 SPATA32 0.129886 0.0406835 0.313224674 MS4A8 0.122195 0.0382744 0.313223945 GATA1 0.11051 0.0346142 0.313222333 PLET1 0.105506 0.0330468 0.313221997 CERS4 0.263578 0.0825579 0.313219996 LOC102546294 0.149837 0.0469318 0.313219031 ADHFE1 0.167663 0.0525152 0.313218778 PLD6 0.660666 0.206932 0.313217269 KIF9-AS1 0.182997 0.0573177 0.31321661 TMEM232 0.143491 0.0449437 0.31321616 FSIP1 0.164082 0.0513931 0.313215953 OLAH 0.288299 0.0902996 0.3132151 VWA5B2 0.150156 0.0470309 0.313213591 VWDE 0.160176 0.0501691 0.313212341 GLS2 0.136009 0.0425993 0.31320942 SRPK3 0.167173 0.0523587 0.313200696 FOLR1 0.186807 0.0584953 0.31313227 HTN1 4.41658 1.36284 0.308573602 SPEG 0.113185 0.0349 0.308344745 FAM90A1 0.188294 0.0579046 0.307522279 PLA1A 0.419191 0.128706 0.307034264 SLC25A21-AS1 0.222053 0.0680441 0.306431798 ATP2C2 0.137715 0.0421863 0.306330465 SLITRK6 1.54935 0.473993 0.305930229 UGT1A3 0.429094 0.128492 0.299449538 LOC100507564 0.307664 0.0919505 0.298866621 TMEM27 1.84651 0.546235 0.295820223 LINC01139 1.8068 0.532638 0.294796325 FOXD4L3 0.156885 0.0460679 0.293641202 GPR124 0.131425 0.0385911 0.293635914 ANKS1B 0.50058 0.14538 0.290423109 TRAF3IP3 0.253437 0.0721874 0.284833706 BHLHE40-AS1 0.893064 0.251769 0.281915966 NLRP13 0.161304 0.0454706 0.281893815 EGFL8 0.712922 0.200721 0.281546929 NFATC4 0.698519 0.196585 0.281431142 ERICH2 2.45654 0.688856 0.280417172 HGF 0.248915 0.0690935 0.277578692 NAALADL2 0.172691 0.0477257 0.276364721 CCDC110 0.5126 0.138513 0.270216543 KRTAP5-10 0.380358 0.102119 0.268481273 KCNIP4 0.179 0.0479976 0.268143017 LOC283038 0.146657 0.0386124 0.263283716 POU6F2 0.589037 0.154935 0.263031015 PCDHGB4 0.118221 0.0302964 0.256269191 ARHGAP8 0.131892 0.0333634 0.252959998 NPM2 1.20383 0.303468 0.252085427 SH2D3C 0.152108 0.0381112 0.250553554 RHCG 0.213042 0.0525711 0.246764018 MAF 0.330351 0.0809708 0.245105358 ULK4P3 0.175027 0.0425763 0.243255612 PPEF1 0.285327 0.0691736 0.242436222 PRKCZ 0.133739 0.0319647 0.239008068 TBC1D10C 0.320732 0.0763408 0.238020528 LOC646626 0.305714 0.0724074 0.236846857 LOC100422556 0.679709 0.159694 0.23494466 PTTG3P 0.440566 0.103504 0.234934153 CALY 0.237443 0.0557806 0.234922066 TAS2R43 0.225226 0.0529105 0.234921812 GNMT 0.214922 0.0504897 0.234921041 APOOP5 0.219078 0.051466 0.234920896 SPATA9 0.182364 0.0428407 0.234918624 LINC01361 0.142496 0.0334748 0.234917471 TAS2R13 0.131457 0.0308814 0.23491636 TTLL13 0.118224 0.0277727 0.234915922 TTTY10 0.13227 0.0310723 0.234915703 DLEU2L 0.129687 0.0304655 0.234915604 APOF 0.126952 0.029823 0.234915559 PPM1J 0.249788 0.058679 0.234915208 PROC 0.119768 0.0281353 0.234915002 ACTG1P4 0.106344 0.0249818 0.234914993 KLRG1 0.238351 0.0559921 0.234914475 PIPOX 0.171958 0.0403952 0.234913176 ABHD12B 0.147571 0.0346653 0.23490591 PTH1R 0.21175 0.0497406 0.234902479 MEIOB 0.13561 0.0315629 0.232747585 NBPF25P 7.05834 1.60722 0.227705098 LOC101928674 0.332561 0.0743977 0.223711439 GUSBP9 1.24003 0.276818 0.223234922 LINC00957 1.77283 0.390932 0.220512965 LOC100270746 0.813826 0.17648 0.216852251 DNASE1L2 0.542358 0.117609 0.216847544 ALX3 0.479243 0.103922 0.216846151 LRRC70 0.115908 0.0248151 0.214093074 SAMD13 0.17257 0.0366889 0.212603002 LOC100131655 0.385842 0.08057 0.208816044 SLC13A4 0.159199 0.0332425 0.208810985 LOC100506603 0.356437 0.0722498 0.202700056 APOBEC1 0.936059 0.188488 0.201363376 VN1R1 0.483532 0.0973624 0.201356684 GP1BA 0.578856 0.116555 0.20135405 LOC100506076 0.621052 0.123356 0.19862427 CBR3-AS1 0.434174 0.0851612 0.196145324 NRN1L 0.522054 0.0981184 0.187946841 CCL2 0.418584 0.0786699 0.187942922 UPK2 0.315885 0.059367 0.187938649 LINC01099 0.232804 0.0437521 0.187935345 CATSPER3 0.201443 0.0378581 0.187934552 NAA11 0.179114 0.0336614 0.187932825 LOC441455 0.163208 0.0306721 0.187932577 SPNS3 0.139881 0.0262881 0.187931885 LOC100506022 0.109877 0.0206493 0.18793105 FUT7 0.107378 0.0201796 0.187930489 PALM3 0.115297 0.0216678 0.187930302 PPIEL 0.195329 0.0367082 0.187930108 KLHL7-AS1 0.20129 0.0378284 0.187929852 FAM69C 1.21013 0.217743 0.179933561 UGT1A10 3.047 0.540836 0.177497867 LINC00598 0.13751 0.0236128 0.171716966 KIAA0825 0.186855 0.0320029 0.171271307 NBPF9 7.74197 1.22257 0.157914588 LCN12 0.558632 0.0874933 0.156620638 WWTR1-AS1 0.189305 0.0296471 0.156610232 LOC101928103 0.139694 0.0218774 0.156609446 SLC46A2 0.123987 0.0194175 0.156609161 GUCY2EP 0.109971 0.0172223 0.156607651 UNC5A 0.162257 0.0254106 0.156607111 CRHR2 0.105739 0.0165554 0.156568532 PRR4 1.74937 0.264411 0.151146413 TPTE2 0.25911 0.0357904 0.138128208 LOC643486 0.522436 0.0701337 0.13424362 A4GNT 0.210774 0.0282937 0.134237145 HCK 0.170279 0.0228513 0.134199167 CFHR1 0.156915 0.0201067 0.128137527 AIFM3 0.177317 0.0212411 0.119791673 AGR3 0.666259 0.0782616 0.117464229 IGF2 1.32976 0.149223 0.112217994 AMIGO1 0.188489 0.0196793 0.104405562 CTD-2201I18.1 0.170338 0.0177842 0.104405359 THBS4 0.142173 0.0148436 0.104405196 LOC100507391 0.124704 0.0130197 0.104404831 SAMD12-AS1 0.90994 0.0855091 0.09397224 C1orf229 0.230815 0.0216886 0.093965297 N4BP2L1 0.167871 0.0157588 0.093874463 MATN2 0.12413 0.0114949 0.092603722 ACRBP 0.308995 0.0263955 0.085423712 C21orf62 0.139633 0.0119228 0.085386692 PAOX 0.415251 0.0351775 0.084713824 NDUFA4L2 440.826 36.4454 0.082675251 EIF3CL 0.555033 0.00326152 0.005876263 EIF3CL 0.518381 0.00250952 0.004841072 PHOSPHO2-KLHL23 0.189844 0.0007422 0.003909526 BLOC1S5-TXNDC5 0.398702 0.001471 0.003689472 TBC1D3H 0.181731 0.000180422 0.000992797 TMEM256-PLSCR3 0.798666 0.000544486 0.000681744 GPRASP2 0.109732 7.38E-05 0.000672548 TMEM189-UBE2V1 0.641139 0.00041812 0.000652152 KRTAP5-2 0.10903 6.40E-06 5.87E-05 FAM156B 0.573796 1.39E-05 2.42E-05 BLOC1S1-RDH5 0.88678 7.18E-06 8.10E-06 HLX-AS1 0.251215 6.94E-07 2.76E-06 RAD51L3-RFFL 0.555319 1.22E-06 2.20E-06 LOC100287944 0.121227 2.03E-08 1.67E-07 MIA 0.10396 3.55E-09 3.41E-08 ZNF559-ZNF177 0.32187 8.82E-13 2.74E-12 PCNA-AS1 0.136253 9.81E-16 7.20E-15 FKBP1A-SDCBP2 3.52807 6.51E-25 1.85E-25 LOC100652999 0.221191 8.25E-36 3.73E-35 URGCP-MRPS24 0.250538 9.74E-37 3.89E-36 STX16-NPEPL1 0.147835 2.40E-85 1.62E-84 DEAR 0.520359 6.37E-152 1.22E-151 APOD 0.251269 0 0 BEST2 0.110811 0 0 BEX5 0.372003 0 0 BPIFA2 0.109414 0 0 C10orf131 0.143855 0 0 C11orf97 0.111415 0 0 C17orf105 0.146989 0 0 C5orf66-AS1 0.144439 0 0 CAPZA3 0.106275 0 0 CARD17 0.327183 0 0 CASQ1 0.107833 0 0 CD52 0.144481 0 0 CDRT15 0.12184 0 0 CECR5-AS1 0.21204 0 0 CGB1 0.10315 0 0 CGB8 0.148123 0 0 CLEC7A 0.14277 0 0 CRYAA 0.14859 0 0 CSN1S2AP 0.159133 0 0 CST6 0.110142 0 0 CXorf31 0.138266 0 0 CXorf65 0.139307 0 0 CYCSP52 1.03064 0 0 CYP46A1 0.151646 0 0 DEPDC1-AS1 0.179141 0 0 EFHB 0.125622 0 0 EFHD1 0.101359 0 0 ERAS 0.147214 0 0 FAM83C-AS1 0.244558 0 0 FLJ21408 0.112194 0 0 FLJ25758 0.111879 0 0 FLJ35934 0.169234 0 0 GHRL 0.327618 0 0 GJB1 0.100926 0 0 GLUD1P7 0.153202 0 0 HCRT 0.356507 0 0 HIF1A-AS1 0.100681 0 0 HIST1H2BM 0.175486 0 0 HIST1H2BO 0.163039 0 0 HIST1H3A 0.161945 0 0 HIST1H3G 0.163039 0 0 HOXC-AS3 0.244558 0 0 HYPM 0.292468 0 0 IGSF23 0.11785 0 0 KLHDC9 0.105091 0 0 KRTAP5-4 0.143142 0 0 KRTAP5-7 0.265236 0 0 LINC00545 0.21064 0 0 LINC00853 0.196869 0 0 LINC01118 0.110545 0 0 LINC01237 0.357388 0 0 LINC01265 0.153307 0 0 LINC01341 0.151871 0 0 LOC100128568 0.10307 0 0 LOC100129083 0.144525 0 0 LOC100131626 0.245287 0 0 LOC100506082 0.17422 0 0 LOC100506688 0.102782 0 0 LOC101927062 0.142349 0 0 LOC101927604 0.154785 0 0 LOC101928455 0.191479 0 0 LOC101928530 0.389129 0 0 LOC101929125 0.450711 0 0 LOC101929196 0.106956 0 0 LOC101929452 0.134411 0 0 LOC101929584 0.300782 0 0 LOC101929746 0.507742 0 0 LOC102060414 0.163178 0 0 LOC102723513 0.187761 0 0 LOC102723769 0.139493 0 0 LOC102724691 0.102412 0 0 LOC283440 0.12062 0 0 LOC400043 0.157466 0 0 LOC644145 0.222218 0 0 LOC728739 0.106962 0 0 LOC729930 0.2064 0 0 LYG2 0.138333 0 0 MGP 0.117804 0 0 MIR1248 288.82 0 0 MIR6740 68.6911 0 0 MOGAT1 0.104205 0 0 MT1L 0.189231 0 0 MUCL1 0.151756 0 0 NAPSB 0.124727 0 0 NKG7 0.294428 0 0 NLGN4Y-AS1 0.133666 0 0 NTF3 0.193345 0 0 OR52N2 0.121263 0 0 OR5E1P 0.137871 0 0 OVOL1-AS1 0.129361 0 0 OVOL2 0.208876 0 0 PCAT2 0.119425 0 0 PCP4L1 0.115364 0 0 PLA2G4D 0.141118 0 0 RAB33A 0.102869 0 0 RETNLB 0.120019 0 0 RFTN1 0.102083 0 0 RNASE8 0.164148 0 0 RPS6KA2-AS1 0.279475 0 0 SALL4 0.101765 0 0 SCGB2A2 0.288099 0 0 SCGB3A2 0.278128 0 0 SFTPC 0.144575 0 0 SLURP1 0.131838 0 0 SNAR-A1 2.00541 0 0 SNAR-A11 2.20529 0 0 SNAR-A14 2.20529 0 0 SNAR-A14 2.20529 0 0 SNAR-A14 2.20529 0 0 SNAR-A2 2.00541 0 0 SNAR-A3 2.20529 0 0 SNAR-A3 2.20529 0 0 SNAR-A3 2.20529 0 0 SNAR-A4 2.20529 0 0 SNAR-A7 2.20529 0 0 SNAR-A9 2.20529 0 0 SNORA22 9.7687 0 0 SNORA29 6.96356 0 0 SNORA70 9.19605 0 0 SNORA74B 1.06763 0 0 SNORA7B 7.33996 0 0 SNORA84 10.3957 0 0 SNORD94 8.19032 0 0 SOCS2-AS1 0.239443 0 0 STATH 0.12091 0 0 TAC4 0.122753 0 0 TEX19 0.109177 0 0 TGIF2LY 0.139738 0 0 TMEM252 0.134857 0 0 TMEM262 0.156163 0 0 TMEM31 0.171917 0 0 TMEM61 0.104093 0 0 TNP1 0.209729 0 0 TOMM20L 0.10989 0 0 TRERNA1 0.113516 0 0 UBD 0.117706 0 0 UBE2NL 0.190103 0 0 VPREB3 0.466145 0 0 WFDC5 0.113811 0 0 Supplementary Table S6 Up Regulated Genes in NDUFA4L2 Knockdown HCC cells Gene NTC (FPKM) shL2-90 (FPKM) fold change OR2J3 0 0.100197 Inf PYY2 0 0.100755 Inf RNASE6 0 0.101774 Inf CEACAM20 0 0.102574 Inf ACTA1 0 0.10282 Inf LOC284648 0 0.102976 Inf FCRLA 0 0.103208 Inf HSD52 0 0.103877 Inf LOC101928259 0 0.105926 Inf SYNJ2-IT1 0 0.105926 Inf C16orf71 0 0.107126 Inf SAA2 0 0.107181 Inf RSPH9 0 0.107455 Inf LOC101060091 0 0.108205 Inf LOC649330 0 0.108485 Inf EVA1A 0 0.110133 Inf LINC00189 0 0.110742 Inf LOC284009 0 0.111951 Inf PGC 0 0.112819 Inf LINC01344 0 0.113352 Inf LOC101929625 0 0.114499 Inf WFDC2 0 0.114789 Inf LIPF 0 0.1156 Inf LINC01091 0 0.115965 Inf SPANXN5 0 0.116262 Inf TAS2R42 0 0.117045 Inf LOC102724246 0 0.118423 Inf SPINK7 0 0.119957 Inf NBEAP1 0 0.120276 Inf CD200R1L 0 0.120741 Inf LGALS2 0 0.127 Inf PYDC1 0 0.127022 Inf LHB 0 0.129 Inf LOC649352 0 0.128828 Inf AANAT 0 0.129931 Inf PPP4R4 0 0.130882 Inf TTTY14 0 0.131827 Inf CXorf58 0 0.13209 Inf FGF22 0 0.132599 Inf PRAC2 0 0.133374 Inf LTB 0 0.134035 Inf SPERT 0 0.135641 Inf LOC100505984 0 0.136186 Inf C9orf57 0 0.136576 Inf MMP3 0 0.136599 Inf OPA1-AS1 0 0.137009 Inf LINC01146 0 0.137288 Inf CLDN24 0 0.138188 Inf CITED1 0 0.139189 Inf LOC100130417 0 0.139541 Inf LPP-AS1 0 0.139972 Inf CHI3L2 0 0.142699 Inf GPR19 0 0.14399 Inf LINC01214 0 0.144894 Inf TNFRSF4 0 0.145619 Inf LOC101927931 0 0.147728 Inf LOC101928604 0 0.148162 Inf HIST1H3I 0 0.148211 Inf LOC101927478 0 0.148211 Inf LINC01213 0 0.149666 Inf CCER2 0 0.153352 Inf CST1 0 0.153862 Inf CYP11A1 0 0.154316 Inf DNAJB5-AS1 0 0.15734 Inf CASP5 0 0.159476 Inf ECSCR 0 0.160693 Inf C2orf48 0 0.162715 Inf LINC01135 0 0.1651 Inf STH 0 0.165521 Inf LOC101927164 0 0.169838 Inf LOC100133669 0 0.170696 Inf PPP1R14A 0 0.172643 Inf NUCB1-AS1 0 0.173095 Inf KRT13 0 0.17892 Inf B3GNT7 0 0.183438 Inf LINC00993 0 0.18808 Inf MT1A 0 0.201467 Inf MT1G 0 0.201467 Inf C6orf52 0 0.20148 Inf DOCK9-AS1 0 0.205093 Inf SPARC 0 0.21179 Inf KLRC3 0 0.212173 Inf TAS2R50 0 0.218542 Inf EIF1AX-AS1 0 0.21886 Inf TNKS2-AS1 0 0.219912 Inf AWAT1 0 0.221225 Inf LOC102723510 0 0.225575 Inf XCL2 0 0.230161 Inf CYP2C19 0 0.243417 Inf NEBL-AS1 0 0.264423 Inf C1orf234 0 0.267546 Inf PAGE2B 0 0.269136 Inf LOC102723544 0 0.273192 Inf CLRN3 0 0.279542 Inf TAL2 0 0.285082 Inf PPIAP30 0 0.298892 Inf HIST1H3F 0 0.307479 Inf RIIAD1 0 0.319389 Inf HIST1H2BL 0 0.321653 Inf LOC101928784 0 0.355808 Inf LOC101928737 0 0.363726 Inf LOC101926895 0 0.378159 Inf SCARNA5 0 0.412889 Inf PINLYP 0 0.447292 Inf CPSF4L 0 0.476137 Inf APOC3 0 0.501062 Inf LOC101928943 0 0.541998 Inf LOC101929760 0 0.542003 Inf PSPN 0 0.604705 Inf GNG8 0 0.868774 Inf SNORA23 0 1.33735 Inf SNORA59A 0 1.92365 Inf SNORA59B 0 1.92365 Inf SNORA70G 0 5.98872 Inf SNORD97 0 5.98872 Inf SNORA71C 0 7.38499 Inf MIR5572 0 7.81026 Inf SNORA14B 0 8.77742 Inf SNORA48 0 8.77742 Inf SNORA27 0 16.3691 Inf SNORA52 0 18.6572 Inf MIR508 0 50.2134 Inf KCNRG 2.78E-89 0.178781 6.43E+87 RFPL3 1.30E-35 0.150813 1.16E+34 SPECC1L-ADORA2A 5.49E-31 0.398123 7.25E+29 DNAJC25-GNG10 1.45E-26 0.354015 2.44E+25 MIA-RAB4B 5.14E-21 0.119139 2.31788E+19 SNORA81 7.26E-08 3.43252 47279889.81 POC1B-GALNT4 2.79E-08 0.346056 12403440.86 FAM27A 5.90E-07 0.399323 676818.6441 SPTY2D1-AS1 4.78E-07 0.109377 228822.1757 HSPB2-C11orf52 4.63E-06 0.235654 50897.19222 INS-IGF2 2.19E-05 0.464919 21229.17808 LOC100132111 3.92E-05 0.190653 4863.596939 IPO11-LRRC70 0.000123508 0.154756 1253.003854 C15orf38-AP3S2 0.000113646 0.138759 1220.975661 FAM45A 0.00134211 1.47522 1099.17965 LOC100101148 0.000826813 0.745899 902.1374845 FAM72D 0.000328517 0.268763 818.1098695 GSTT2 0.000730775 0.54786 749.6972392 GSTT2 0.000747438 0.500487 669.6033651 COMMD3-BMI1 0.00105507 0.617066 584.8578767 JMJD7-PLA2G4B 0.000688936 0.290214 421.2495791 CCDC180 0.0059698 0.115718 19.38389896 LOC102724550 0.172887 3.24906 18.79296882 SERPINA3 0.0339535 0.414764 12.21564787 PPP1R14D 0.0822827 0.927904 11.27702421 AGT 0.159896 1.74661 10.92341272 SLAMF9 0.0489262 0.509019 10.40381227 IBSP 0.0339296 0.350707 10.33631401 SLC5A5 0.014145 0.146204 10.33609049 LCN2 1.25902 12.8054 10.17092659 C14orf105 0.0164715 0.154922 9.405457912 DNAJB5 0.0211701 0.198956 9.397971668 LOC101927780 0.0290121 0.265158 9.139565905 BZRAP1-AS1 0.0238697 0.2173 9.103591583 UCN2 0.330015 2.99768 9.083465903 PPAN-P2RY11 0.150305 1.35997 9.048068927 RMRP 2.39926 21.6629 9.028992273 APOBEC3G 0.0144846 0.129301 8.926791213 FAM157B 0.0217651 0.184069 8.457071183 LOC101928335 0.025103 0.212294 8.4569175 S100A9 0.237671 1.89847 7.987806674 DACT3-AS1 0.0425305 0.335601 7.890831286 CTSE 0.0251521 0.189097 7.518139638 DGCR10 0.0637625 0.479338 7.517553421 TM4SF4 0.0335513 0.252216 7.517324217 KLHDC7B 0.0170802 0.128395 7.51718364 GBP1 0.0167301 0.125763 7.517169652 DKK1 0.117935 0.858844 7.282350447 GGT5 0.021625 0.155777 7.203560694 C1orf177 0.0314624 0.22383 7.114206164 PPP1R1B 0.0386027 0.271926 7.044222295 LOC101926888 0.11767 0.814265 6.919903119 CYP2D6 0.0792079 0.523895 6.614176111 ENPP2 0.124017 0.819605 6.608811695 LSMEM2 0.0453851 0.298661 6.580595834 TUSC8 0.0531963 0.349914 6.577788305 CD226 0.0195329 0.128479 6.577569127 DCAF4L1 0.0209349 0.137699 6.577485443 SOX18 0.785 5.10553 6.503859873 NAAA 0.03086 0.199243 6.456351264 CXCL2 0.0933924 0.570432 6.107905997 PRR15L 0.0715922 0.437273 6.107830183 DNER 0.0310641 0.18973 6.107693447 UCA1 1.25877 7.66715 6.090985645 CCAT1 0.128495 0.776186 6.040593019 APOA1 0.531203 3.08861 5.814368518 PLCB2 0.0215776 0.122391 5.672132211 SUGT1P1 0.0806326 0.454629 5.638277818 LOC100289656 0.033292 0.187706 5.638171332 CELP 0.0296073 0.16693 5.638136541 NR0B2 0.0438074 0.246988 5.638042888 C6orf164 0.0347373 0.195849 5.638002954 DUSP2 0.0318218 0.179411 5.637990309 TNRC18P1 0.0280251 0.158004 5.637945984 ISM1 0.0198961 0.112172 5.637888832 TNFRSF9 0.0413594 0.233178 5.637847744 GPBAR1 0.0397846 0.223655 5.621647572 LYZ 0.7881 4.275 5.424438523 CYP2C18 0.263102 1.41086 5.362406975 C3orf65 0.0806038 0.429193 5.324724145 ZNF365 0.0238603 0.126863 5.316907164 OSGEPL1-AS1 0.0689876 0.365309 5.29528495 RGPD6 0.0686252 0.357374 5.207620524 ACKR2 0.0345402 0.178506 5.168065037 SELPLG 0.0402508 0.205457 5.104420285 DISP2 0.505282 2.56476 5.075898211 PAQR9 0.0996331 0.491509 4.933189874 SERPINA5 0.0889573 0.438842 4.933175805 GLI2 0.0875868 0.432074 4.933094941 ROS1 0.0267654 0.132036 4.933085252 HIPK1-AS1 0.0247546 0.121111 4.892464431 RRAD 0.223012 1.08298 4.856151238 FLNC 1.63346 7.90908 4.841918382 ENG 0.61599 2.98098 4.839331807 CD83 0.0627077 0.296809 4.733214581 SNORD17 1.33018 6.2594 4.705678931 LY6G5C 0.0868891 0.408256 4.698587049 TSACC 0.0832824 0.391308 4.698567765 LINC01133 0.0498377 0.234158 4.698411042 LINC00326 0.0462033 0.217081 4.698387345 AKR7A2P1 0.0417922 0.196355 4.698364767 TMEM121 0.0357429 0.167932 4.698331697 ZNF253 0.0223218 0.104874 4.698277021 LINC00612 0.0236251 0.110997 4.698265827 ZNF585B 0.0239238 0.112399 4.698208479 NBPF25P 1.29832 6.09019 4.690823526 CDHR2 2.21474 10.2811 4.642125035 MIR497HG 0.0800946 0.371025 4.632334764 SLC37A2 0.279157 1.28496 4.603001179 C14orf182 0.114913 0.521895 4.541653251 CYP24A1 3.11244 13.9838 4.492873758 MGAT5B 0.0946723 0.422751 4.465413854 TCTEX1D4 0.132264 0.579999 4.385161495 DSG4 0.070642 0.305341 4.32237196 ROR1 0.229358 0.987061 4.303582173 FXYD2 2.53303 10.8704 4.291461214 DUOXA2 1.06233 4.51042 4.245780501 CCDC17 0.0469328 0.198511 4.229685849 IL7 0.0560411 0.236998 4.229003356 C1QTNF7 0.0461168 0.195013 4.228675884 CCDC28B 0.136567 0.577494 4.228649674 LOC729683 0.0442538 0.187125 4.228450438 GPR115 0.0322069 0.136184 4.228410682 DIRC3 0.0257899 0.10905 4.22839949 NBPF9 1.11281 4.61789 4.149756023 RPPH1 4.24059 17.2726 4.073159631 RFPL3S 0.0994625 0.39847 4.006233505 SLCO1B7 0.054994 0.219621 3.99354475 EPHB2 0.297382 1.18556 3.986656892 FAM83A 0.0624534 0.245334 3.92827292 APOE 1.91046 7.42771 3.887917046 TAPSAR1 0.102031 0.396177 3.882908136 ARHGEF4 0.0967415 0.372867 3.854261098 RGPD6 0.0686247 0.261516 3.810814474 MYL9 0.939391 3.57565 3.806349007 FLT3LG 0.0544303 0.204673 3.760276905 C20orf144 0.120923 0.454547 3.758978854 LOC100505683 0.103736 0.389937 3.758936146 FAM209A 0.0475643 0.17879 3.758911621 LOC102467073 0.072938 0.27416 3.758808851 RBPMS-AS1 0.130639 0.491043 3.758778007 LOC283710 0.0559792 0.210412 3.758753251 DLEU7 0.095523 0.359044 3.758717796 LINC00628 0.086126 0.323721 3.758690755 C11orf96 0.0832953 0.313081 3.758687465 ACOT4 0.0329769 0.123949 3.758661366 FLJ26245 0.0675261 0.253807 3.758650359 EPCAM 0.0311427 0.117054 3.758633644 MAN1C1 0.0323228 0.121488 3.758585271 MCF2L2 0.0397855 0.149536 3.758555253 AVPR2 0.0336768 0.125242 3.718940042 HPN-AS1 0.0642922 0.237601 3.695642706 STXBP6 0.16184 0.58295 3.602014335 RGS20 0.249457 0.896242 3.5927715 STMN3 1.16014 4.09152 3.526746772 EHF 0.109464 0.385714 3.523660747 APITD1-CORT 0.0744073 0.259965 3.493810419 CD14 0.0355089 0.123658 3.482450879 DEFB1 9.50317 33.083 3.481259411 TUBA4B 0.0996378 0.346419 3.476782908 GFPT2 0.237 0.821 3.464135021 FGG 0.0969992 0.334221 3.445605737 FAM46B 0.065597 0.226008 3.445401467 CCDC96 0.0729144 0.251219 3.445396245 CXCL5 0.187105 0.64465 3.445391625 C14orf37 0.0496383 0.171023 3.445383907 RAB3C 1.09283 3.74734 3.429023727 CD79A 1.19696 4.07489 3.404366061 TINAG 0.147509 0.498989 3.382769865 TMEM86A 0.0706006 0.238822 3.382719127 LINC00638 0.143666 0.482127 3.355887962 ZDHHC14 0.239363 0.795863 3.324920727 NARR 0.333166 1.10699 3.322637964 LOC101927322 0.224667 0.746455 3.32249507 HTRA3 0.608961 2.02181 3.320097675 CPLX2 0.502455 1.66752 3.318744962 FAM71F2 0.0345252 0.113581 3.289799914 TNNT2 0.0982351 0.323121 3.289262188 LOC101928794 0.168606 0.554546 3.289005136 NFE2 0.0637665 0.209725 3.288952663 SOCS1 0.0922297 0.303331 3.28886465 GALR2 0.0812572 0.267243 3.288853172 BPIFB2 0.0550883 0.181175 3.288810873 NTN3 0.0530842 0.174583 3.288794029 STAU2-AS1 0.0507886 0.167033 3.288789216 CACNG7 0.0443149 0.145742 3.288780974 CCDC126 0.20925 0.688177 3.288778973 LOC101928437 0.0550125 0.180923 3.288761645 RFTN2 0.0327434 0.107685 3.288754375 FGFR1 0.0402745 0.132 3.277508101 APOB 2.15 6.99804 3.254902326 NKD1 0.473396 1.53304 3.238388157 CD82 0.166705 0.536107 3.215902342 FMNL1 0.432065 1.37916 3.192019719 SHISA9 0.0921279 0.292785 3.178027503 FAM222A 0.519129 1.63108 3.141955082 FRMD1 0.0505769 0.158847 3.140702574 CYTIP 0.14175 0.443988 3.132190476 IHH 0.481476 1.50014 3.115710856 MYO1F 0.493414 1.53413 3.109214574 ICAM2 1.0741 3.33433 3.104301275 RGPD8 0.24715 0.765961 3.09917459 ITGB3 0.703594 2.17501 3.091285599 MFAP3L 0.112034 0.345898 3.087437742 FAM225B 0.0683715 0.210802 3.083185245 OLFM2 0.655643 2.00896 3.064106534 AUNIP 0.0967795 0.295553 3.053880212 CDC25A 0.155135 0.47369 3.053405099 GNRHR2 0.0648361 0.19784 3.051386496 SLC51B 1.56709 4.77116 3.044598587 CHRM4 0.631538 1.91994 3.0401021 ETNK2 0.197492 0.593836 3.006886355 VASH1 0.0559458 0.166714 2.979919851 TNFRSF19 0.0445837 0.132771 2.978016629 MAP1A 0.695842 2.06899 2.973361769 C10orf32-ASMT 0.112061 0.331778 2.960691052 PRICKLE2 0.0413568 0.122131 2.953105656 TEK 0.146578 0.432461 2.950381367 LINC00312 0.301485 0.883199 2.929495663 CASP1 0.167349 0.488411 2.918517589 CSF1 14.4474 42.1604 2.918199814 MTTP 0.823391 2.38748 2.899570192 ATP6V0D2 0.525731 1.52318 2.897261147 PYCRL 0.326627 0.9388 2.874226564 ADAM19 0.579446 1.66544 2.874193626 FAM47E-STBD1 0.0754348 0.216624 2.87167196 SULT1A3 4.16063 11.9397 2.8696856 UNC13A 0.617707 1.767 2.86057953 PTPRS 0.181491 0.519026 2.859789191 DUSP13 0.15059 0.43025 2.857095425 LOC648987 0.256599 0.732774 2.855716507 TRIM29 0.879436 2.50821 2.852066552 TMIGD2 0.0440075 0.125394 2.849377947 MRGPRF 0.0687326 0.193853 2.820393816 AOAH-IT1 0.120019 0.338363 2.819245286 IGFL2 0.10939 0.308396 2.819233934 PNPLA1 0.131594 0.370993 2.819224281 HS1BP3-IT1 0.112456 0.317038 2.819218183 PPP1R32 0.0736655 0.207678 2.819203019 SLC9B1 0.0365535 0.103051 2.819182842 PLAC8L1 0.0870462 0.245397 2.819158102 GPHA2 0.0837168 0.23601 2.819147411 COX7A1 0.081589 0.230011 2.819142286 TYRO3P 0.069566 0.196114 2.819107035 KRTAP2-3 0.21238 0.598721 2.819102552 NBPF18P 0.0578627 0.163119 2.819069971 TCAP 0.182584 0.514717 2.819069579 ENHO 0.0531375 0.149798 2.81906375 USP2-AS1 0.0489262 0.137925 2.81904174 CLDN20 0.139278 0.39263 2.819038183 ZDHHC19 0.041326 0.116499 2.819024343 GNAT2 0.0403562 0.113765 2.819021613 THAP7-AS1 0.0441285 0.124399 2.819017188 LRRC69 0.0418285 0.117915 2.819010961 PRSS50 0.0409743 0.115507 2.819010941 LOC101928283 0.0761793 0.21475 2.819007263 LINC01137 0.383628 1.08145 2.819006955 EP400NL 0.24654 0.694997 2.819003002 PRR16 0.0605238 0.170616 2.818990215 C9orf117 0.0621246 0.175128 2.818979921 OLFML3 0.0870125 0.245286 2.818974285 HMGN2P46 0.0548686 0.154673 2.818971142 SH3PXD2A-AS1 0.208093 0.586608 2.818970364 MINOS1P1 0.0457029 0.128835 2.818967724 ELMO3 0.0617288 0.174011 2.818959708 TAS1R3 0.100856 0.284308 2.81894979 KLHDC7A 0.0591407 0.166713 2.818921656 MUSK 0.0932412 0.262837 2.818893365 SCEL 0.0965 0.272 2.81865285 SLC43A3 0.933188 2.62858 2.816774326 SCG5 0.0899476 0.253208 2.815061213 C1S 3.09459 8.65713 2.797504678 C10orf2 0.404843 1.1289 2.788488377 C15orf48 10.9596 30.5139 2.784216577 ATP8B5P 0.113121 0.311343 2.752300634 ANKRD33B 0.183964 0.50376 2.738361853 SRRM2-AS1 0.0716619 0.196188 2.737689065 LOC202181 0.0986291 0.269605 2.733523879 SLC16A12 0.119023 0.32535 2.733505289 LCN15 0.81589 2.22344 2.725171285 C8orf44-SGK3 0.242046 0.658278 2.719640068 ROPN1L 0.106275 0.288871 2.718146319 SAP30L-AS1 0.117509 0.31745 2.701495205 PMS2P4 0.230055 0.620847 2.698689444 RNF219-AS1 0.115333 0.311107 2.697467334 SENP3-EIF4A1 0.184123 0.494706 2.686823482 ABCB11 0.481189 1.29254 2.686137879 SBK2 0.324556 0.864111 2.66244038 OR7E12P 0.0464261 0.123606 2.6624248 CHAC2 0.261891 0.697262 2.662412989 OTUB2 0.982251 2.60998 2.657141606 KRT7 4.5157 11.9905 2.655291538 IGSF9 0.13679 0.36223 2.64807369 TICAM2 0.0717342 0.189691 2.644359315 RPS10P7 0.496562 1.3124 2.642973083 ACTR3C 0.321871 0.849865 2.640390094 ITGB6 0.189 0.497347 2.631465608 GCSAML 0.0652175 0.171605 2.631272281 LYVE1 0.103412 0.272078 2.631009941 NPHS1 0.0496191 0.130548 2.631002981 LONRF2 0.0665851 0.174525 2.621081894 ADAMTS12 2.21016 5.7856 2.617729033 FGL1 7.12944 18.6404 2.614567203 CEACAM3 0.0483074 0.126091 2.610179807 ELMO1 0.12678 0.330918 2.610175106 RBM14-RBM4 0.752071 1.9623 2.609195142 SULT1A3 4.74866 12.3756 2.606124675 LIPE 0.171916 0.447342 2.602096373 IGFBP1 88.8329 231.028 2.600703118 TSGA10 0.11009 0.285 2.588790989 PID1 0.0789622 0.204045 2.584084537 UGT2B11 0.125545 0.324417 2.584069457 CCR1 0.0769149 0.198751 2.584037683 KCNB1 0.0537385 0.138862 2.584031932 CACNG4 0.177346 0.458267 2.584027833 SLCO2A1 0.142631 0.368562 2.584024511 ZFHX2 0.0427536 0.110475 2.583992927 LINC00520 1.14136 2.9466 2.581656971 POLR2J4 1.13848 2.91813 2.563180732 FAM27E2 0.0553411 0.141557 2.557900006 CISH 0.347636 0.886642 2.550489593 SEMA6B 0.268209 0.684056 2.550458784 KLF2 5.50895 14.0288 2.546546983 TF 37.8995 95.8269 2.528447605 TNFRSF1B 1.49823 3.77783 2.521528737 LOC101927621 0.360462 0.907259 2.516933824 SNHG9 1.04786 2.63011 2.50998225 FKBP6 0.0524029 0.13135 2.506540669 IDH1-AS1 0.45242 1.13378 2.506034216 ECM2 0.0473216 0.118587 2.505980356 C9orf106 0.215228 0.539334 2.505872842 COPZ2 0.193336 0.484471 2.505849919 LRRC29 0.127589 0.319716 2.505827305 ARL14 0.647102 1.62151 2.505802795 CD3G 0.126807 0.317753 2.505800153 DGAT2L6 0.0940362 0.235633 2.505769055 KRT81 0.041554 0.104124 2.505751552 F12 0.0768721 0.192622 2.505746558 JAKMIP1 0.0598118 0.149873 2.505743014 ZNF786 0.373251 0.935263 2.505721351 TNS4 0.283961 0.707659 2.492099267 PVRL4 0.159053 0.394012 2.477237147 UNC13D 1.02714 2.54155 2.474394922 TRIM31 17.6757 43.6893 2.471715406 TAT 0.14901 0.367545 2.466579424 ABCA6 0.0751764 0.185427 2.466558654 GRM8 0.0652795 0.160494 2.458566625 UFSP1 0.292122 0.71371 2.443191543 HSF2BP 0.139395 0.340558 2.443114889 LOC101928100 0.181147 0.442558 2.443087658 LRRC49 0.638462 1.55885 2.441570524 AMOTL1 0.229109 0.558702 2.438586001 SIRPA 0.282158 0.687945 2.438155218 C16orf74 2.82201 6.86358 2.432160056 LHX4 2.45204 5.95652 2.429209964 CC2D2B 0.0575906 0.139781 2.42714957 IL4I1 0.562859 1.36087 2.417781363 GLIPR1 3.04714 7.36698 2.41767034 CCDC65 0.210236 0.508004 2.416351148 SKP1P2 0.197093 0.47623 2.416270492 OAF 9.20207 22.2327 2.416054214 NRARP 1.3959 3.36227 2.408675407 WWC1 0.459497 1.10412 2.402888376 BIN2 0.218077 0.523686 2.401381164 WNT7B 1.81527 4.35501 2.399097655 SHANK3 1.91358 4.58229 2.394616373 CD24 11.9827 28.6927 2.394510419 SERPINA6 0.401213 0.959654 2.391881619 RAB27B 1.79041 4.26546 2.38239286 FER1L6 0.483227 1.15054 2.380951396 RASSF5 1.10501 2.6304 2.380430946 NUAK2 0.506994 1.205 2.376753966 TCF7 1.10335 2.61023 2.365731635 LOXL4 1.60269 3.79085 2.365304582 TMEM88B 0.300673 0.706404 2.349409491 PFKFB1 0.0678528 0.159412 2.349379834 HBA1 0.119129 0.279878 2.349369171 C6orf99 0.206582 0.48533 2.349333437 SLC7A9 0.0635122 0.149208 2.349280926 LINC01006 0.164292 0.385967 2.349274463 SNHG15 0.610313 1.43379 2.349269965 LOC100506499 0.304193 0.71463 2.349265105 LOC100130987 0.142004 0.333604 2.349257767 LOC100506321 0.133168 0.312844 2.349243061 ERICH4 0.124395 0.292234 2.349242333 OR1F1 0.12553 0.2949 2.349239226 CETP 0.0705408 0.165716 2.349222011 PSMB9 0.109914 0.258211 2.349209382 RXFP4 0.0988568 0.232235 2.349206124 S100A14 0.108429 0.254722 2.349205471 ALX1 0.0858955 0.201784 2.349180108 SOX15 0.236392 0.555325 2.349170023 LINC00862 0.46405 1.09013 2.349164961 CEACAM16 0.126701 0.297641 2.349160622 ZBTB32 0.0538561 0.126516 2.349148936 LOC101926975 0.0467456 0.109812 2.349140882 HOXD1 0.0534081 0.125463 2.349138052 HBEGF 0.484566 1.13831 2.349133039 ZNF311 0.076245 0.179109 2.349124533 PROSER2-AS1 0.0645432 0.15162 2.349124307 DUOX2 1.33362 3.12914 2.346350535 APOM 0.268018 0.62729 2.340477132 SLC43A2 1.08447 2.53148 2.334301548 COL17A1 4.48036 10.4527 2.333004491 FAM225A 0.111183 0.25917 2.331021829 G0S2 21.058 48.7837 2.316635008 EGOT 0.485187 1.12225 2.313025699 SCARA3 0.723848 1.67425 2.312985599 CEBPA 2.17344 5.0229 2.311036882 KCNE3 1.77776 4.10592 2.309603096 CPLX1 0.269119 0.620702 2.306422066 PRAP1 9.28084 21.3565 2.30113869 OTUD7A 0.0503301 0.115604 2.296915762 USP2 0.19267 0.440521 2.286401619 HIST1H2AI 1.13361 2.58725 2.282310495 RPRM 0.259445 0.592066 2.282048218 LAG3 0.185182 0.422591 2.282030651 LOC100133920 0.163488 0.373025 2.281665933 AIM1L 0.389152 0.887401 2.280345469 RARRES1 0.139053 0.317076 2.280252853 GCKR 0.561247 1.27917 2.279156949 CACNA2D1 0.38256 0.867686 2.26810435 NES 18.8534 42.7194 2.265872469 LGR5 0.0570331 0.129 2.261844438 PPP1R1C 0.33065 0.747047 2.259328595 EDAR 0.0595621 0.134321 2.255142112 KBTBD8 0.0533816 0.120383 2.255140348 SPOCK1 0.0517189 0.116633 2.255133036 ITGAM 0.0526808 0.118764 2.254407678 NOS1AP 0.139488 0.313517 2.247627036 SEPT5-GP1BB 0.218824 0.491788 2.247413446 INHBB 7.2359 16.2404 2.244420183 PLA2G4C 5.169 11.5897 2.242155156 PAPLN 0.310457 0.695327 2.239688588 CX3CL1 0.372649 0.831626 2.231660356 LOC100129316 0.227617 0.50796 2.231643506 P2RX5 0.938068 2.0902 2.228196677 CCL20 3.49335 7.78132 2.227466472 PRKCH 0.274398 0.610665 2.22547176 MMP19 0.0588033 0.130784 2.224092866 KNG1 0.103527 0.230199 2.223564867 VILL 0.607614 1.3495 2.2209824 C15orf52 7.46776 16.5215 2.212376938 FMNL3 1.08592 2.40081 2.21085347 TAGLN 1.78221 3.92869 2.204392299 MIR3648 10.3871 22.8913 2.203820123 FAM89A 3.41304 7.50603 2.199221222 ST5 0.703538 1.54562 2.196924686 LAMA4 3.88885 8.52864 2.193100788 DLG3-AS1 0.629178 1.37975 2.19294063 HBA2 0.166737 0.365609 2.192728669 TTC9B 0.215228 0.471917 2.192637575 LOC100506860 0.559057 1.2258 2.192620788 POU2F3 0.0528871 0.115961 2.192614078 NLRC4 0.0470323 0.103123 2.192599554 EVI2A 0.053555 0.117424 2.19258706 TGFBR3L 0.13324 0.29214 2.192584809 WDR88 0.0931869 0.204316 2.192539939 C15orf27 0.0648607 0.142209 2.192529529 PCDHGB8P 0.080201 0.175843 2.192528771 CEL 0.163104 0.357609 2.192521336 LOC440600 0.059272 0.129955 2.192519233 LOC101928295 0.0467318 0.10246 2.192511309 RTN4RL1 0.048278 0.10585 2.192510046 ASPHD2 0.045988 0.100829 2.192506741 C10orf25 0.0950315 0.208357 2.192504591 DLGAP1 0.0699962 0.153394 2.191461822 C4BPB 0.75773 1.6589 2.189302258 ACTR3B 0.588643 1.28702 2.186418593 PDZK1IP1 1.23351 2.69418 2.184157404 PTGIS 0.55855 1.21629 2.177584818 TRIML2 0.682901 1.48394 2.172994329 MMRN2 1.08148 2.34857 2.17162592 ARSB 2.93193 6.35524 2.167596089 ACOX2 0.405553 0.878598 2.166419679 HHIPL2 2.34529 5.07616 2.164406108 CLDN1 1.92304 4.14272 2.154255762 CXCL17 6.3267 13.6175 2.15238592 RGPD2 0.137373 0.295674 2.152344347 TRPM6 0.0834935 0.179346 2.148023499 EP300-AS1 0.24472 0.525615 2.147822001 LINC00926 0.143788 0.308824 2.14777311 FABP5 1.7653 3.7898 2.146830567 BATF2 0.954148 2.04602 2.144342387 SLX1A-SULT1A3 0.592998 1.27026 2.142098287 STK31 0.19902 0.425456 2.137754999 CTRL 0.524336 1.11979 2.135634402 SULT1C2P1 0.311174 0.664539 2.135586521 LRG1 3.74275 7.97637 2.131152228 TNFAIP8L3 0.346222 0.737413 2.129884872 THNSL2 0.106559 0.226815 2.128539119 LOC101929162 0.126557 0.269142 2.126646491 SRGN 1.86881 3.97208 2.125459517 LGR6 0.0910441 0.19276 2.117215723 TTYH1 0.114218 0.241494 2.114325238 RBP4 0.254376 0.537831 2.11431503 TAS2R38 0.198324 0.419314 2.114287731 REP15 0.199145 0.421048 2.114278541 IL1B 0.145236 0.307065 2.114248533 YPEL4 0.124249 0.262693 2.114246392 NAP1L5 0.215665 0.455966 2.114232722 NIPAL1 0.572621 1.21065 2.11422564 RGS16 0.0852183 0.18017 2.114217251 BGN 0.254305 0.537655 2.114213248 FAM155B 0.350454 0.740929 2.114197584 C1orf101 0.0671851 0.141875 2.111703339 UBAC2-AS1 0.140061 0.29534 2.108652658 SLCO2B1 0.44963 0.945171 2.1021084 IL18R1 0.234607 0.492765 2.100384899 NME1-NME2 0.842879 1.76962 2.099494708 C9orf24 0.19315 0.404719 2.095361118 KIAA1324 0.0631721 0.131908 2.088073691 WDR62 0.232372 0.484793 2.086279758 BMP6 6.30893 13.1152 2.078831117 PAQR5 3.0074 6.22023 2.068308173 LINC00656 0.830601 1.71706 2.0672501 LCA5L 0.109827 0.227039 2.067242117 IGLON5 0.575554 1.1898 2.067225664 LHX1 0.0738716 0.152709 2.067222045 PRTFDC1 0.265717 0.549296 2.067221894 LOC100506472 0.0709334 0.146635 2.067220801 CSF2RA 0.11899 0.24573 2.065131524 CSF2RA 0.11899 0.24573 2.065131524 MMP15 0.841075 1.73444 2.062170437 F2 4.00792 8.25828 2.060490229 C3 1.01595 2.09285 2.05999311 LOC90834 0.68508 1.40818 2.055497168 PLLP 1.38078 2.83396 2.052434131 MMP24 4.12695 8.46507 2.051168539 TRPM8 0.247424 0.506496 2.047077082 VGF 0.909989 1.86216 2.046354406 ABCC6P1 0.16037 0.327976 2.045120658 ZBTB49 0.295393 0.604113 2.045116167 C2CD4D 0.0937161 0.191346 2.041762301 TAS2R14 0.369369 0.752036 2.036001938 TCN1 0.207079 0.421601 2.035942804 GMDS-AS1 0.204009 0.415349 2.035934689 HSPA6 0.0582444 0.11858 2.035903881 FUZ 0.129387 0.262488 2.028704584 PIK3R3 0.654546 1.32781 2.028596921 C10orf90 0.629185 1.27577 2.027654823 NBPF8 1.99432 4.03467 2.023080549 HAUS7 0.860705 1.73688 2.017973638 LOC100126784 1.11056 2.23974 2.016766316 BTG2 13.9573 28.1454 2.01653615 PARGP1 0.434648 0.87562 2.014549705 XCL1 0.564041 1.13574 2.013577027 ZCWPW2 0.226647 0.456369 2.013567354 LINC00896 0.165701 0.333646 2.013542465 LINC00565 0.146157 0.294293 2.013540234 SP140 4.77428 9.60482 2.011783976 SLC4A11 7.1224 14.3287 2.011779737 FBXO6 1.11886 2.25055 2.011467029 SPOCK2 8.47741 17.0444 2.010566907 ZNF177 0.483736 0.972252 2.009881423 CYB5A 3.68633 7.40358 2.008387746 TMEM204 0.401 0.805 2.007481297 FAM105A 0.308121 0.618524 2.007406181 TGM2 25.3135 50.7066 2.003144567 ABCG2 1.94455 3.89337 2.002195881 CRABP2 40.3014 80.6342 2.000779129 Supplementary Table S7 Pathway Enrichment Analysis of NDUFA4L2 Knockdown HCC cells Down-regulated genes Annotation Cluster 1 Count P_Value GOTERM_BP_ALL regulation of membrane potential 12 5.10E-05 GOTERM_BP_ALL membrane depolarization 7 1.50E-04 GOTERM_BP_ALL cellular ion homeostasis 19 3.10E-04 GOTERM_BP_ALL cellular chemical homeostasis 19 3.70E-04 GOTERM_BP_ALL ion homeostasis 19 8.70E-04 GOTERM_BP_ALL regulation of system process 16 8.80E-04 GOTERM_BP_ALL cellular homeostasis 19 3.60E-03 GOTERM_BP_ALL chemical homeostasis 20 4.40E-03 GOTERM_BP_ALL regulation of neurotransmitter transport 4 1.30E-02 GOTERM_BP_ALL regulation of biological quality 41 1.30E-02 GOTERM_BP_ALL regulation of synaptic transmission 8 1.50E-02 GOTERM_BP_ALL regulation of transmission of nerve impulse 8 2.30E-02 GOTERM_BP_ALL regulation of neurological system process 8 2.70E-02 GOTERM_BP_ALL homeostatic process 23 3.00E-02 GOTERM_BP_ALL cellular metal ion homeostasis 9 3.40E-02 GOTERM_BP_ALL metal ion homeostasis 9 4.30E-02 Annotation Cluster 2 Count P_Value GOTERM_BP_ALL multicellular organismal process 111 1.30E-04 GOTERM_BP_ALL tissue development 26 9.40E-04 GOTERM_BP_ALL system development 64 2.00E-03 GOTERM_BP_ALL multicellular organismal development 75 2.50E-03 GOTERM_BP_ALL anatomical structure development 67 3.60E-03 GOTERM_BP_ALL developmental process 79 5.80E-03 GOTERM_BP_ALL organ development 47 1.30E-02 GOTERM_BP_ALL cell differentiation 43 2.70E-02 GOTERM_BP_ALL cellular developmental process 44 3.30E-02 Annotation Cluster 3 Count P_Value GOTERM_BP_ALL cell adhesion 23 1.50E-02 GOTERM_BP_ALL biological adhesion 23 1.50E-02 GOTERM_BP_ALL cell-cell adhesion 11 3.90E-02

Up-regulated genes Annotation Cluster 1 Count P_Value GOTERM_BP_ALL response to external stimulus 61 8.80E-13 GOTERM_BP_ALL response to wounding 38 6.40E-09 GOTERM_BP_ALL inflammatory response 27 9.20E-08 GOTERM_BP_ALL defense response 39 1.00E-07 GOTERM_BP_ALL response to stress 72 1.60E-06 GOTERM_BP_ALL response to stimulus 122 5.60E-06 Annotation Cluster 2 Count P_Value GOTERM_BP_ALL defense response 39 1.00E-07 GOTERM_BP_ALL immune system process 45 7.40E-05 GOTERM_BP_ALL immune response 34 1.40E-04 Annotation Cluster 3 Count P_Value GOTERM_BP_ALL chemotaxis 16 7.70E-06 GOTERM_BP_ALL taxis 16 7.70E-06 GOTERM_BP_ALL locomotion 22 1.90E-03 GOTERM_BP_ALL cell chemotaxis 6 2.30E-03 GOTERM_BP_ALL locomotory behavior 16 2.80E-03 GOTERM_BP_ALL behavior 22 5.10E-03 SUPPLEMENTARY MATERIALS AND METHODS

Quantitative real-time PCR Trizol reagent (Invitrogen) was used to extract total RNA. cDNA was synthesized by GeneAmp® Gold RNA PCR Core Kit (Life Technologies). Quantitative real-time PCR (qRT-PCR) was performed with SYBR Green PCR Master Mix (Life Technologies) with the according primers. Sequences of primers are provided in Supplementary Table S2.

ChIP assay MHCC97L cells were cross-linked with formaldehyde and lysed with SDS buffer and followed by sonication. Sheared DNA was pre-cleared with salmon sperm DNA/ A agarose slurry (Merck Millipore) and immuno-precipitated with against HIF-1α (Abcam), HIF-1β (Abcam) or IgG (Santa Cruz). Agarose beads were incubated with /protein/DNA complex and washed with low-salt buffer, high-salt buffer and LiCl wash buffer according to the manufacturer’s protocol (Millipore). DNA was eluted in 1%

SDS/0.1M NaHCO3, de-cross-linked with 0.2M NaCl and extracted by phenol-chloroform.

Establishment of HIF or NDUFA4L2 knockdown and HIF knockout HCC cells pLKO.1-puro vector encompassing short hairpin RNAs (shRNAs) against NDUFA4, NDUFA4L2, HIF-1α, HIF-2α and non-target control (NTC) (Sigma Aldrich) or pQCXIN retroviral vector encoding constitutively active HIF-1α (CA5) were stably transfected into human HCC cell lines as previously described (1, 2). Small interfering RNAs (siRNAs) against NDUFA4L2 and NTC were generated in human HCC cell lines according to the manufacturer’s instruction (Dharmacon, GE Healthcare). pLenti6-V5-NDUFA4L2 construct was cloned by PCR amplification of NDUFA4L2 from MHCC97L cells using BamHI and XhoI restriction sites. HIF-1α specific TALE domains were designed by E-TALEN software (3), assemble and clone into pTALEN v2 vector by “TALE Toolbox” (4). Frame-shift mutations of HIF-1α in the stable HIF-1α KO cells were identified by SURVEYOR mutation detection (Transgenomic. Inc). Homozygous knockout of HIF-1α was confirmed by DNA sequencing. Sequences of shRNAs and siRNAs are provided in Supplementary Table S3.

Mitochondrial membrane potential and mitochondrial mass measurement

Cells were cultured in 20% and 1% O2 for 24 hrs. For mitochondrial membrane potential measurement, cells were stained with 20 μM tetramethylrhodamine ethyl ester (TMRE; Sigma) for flow cytometry analysis. For mitochondrial mass measurement, cells were stained with 10 nM nonyl acridine orange (NAO) for flow cytometry analysis.

Migration assay

Conditioned medium (CM) was generated from MHCC97L cells exposed to 1% O2 for 48 hrs. 2 x 106 cells in serum free DMEM (Life Technologies) were seeded on the upper chamber of 24-well transwell inserts (Merck Millipore) and CM was added in the lower chamber. After 22 hrs, migrated cells were collected in the lower membrane of the transwell inserts. Migrated cells were fixed with methanol and stained with 0.08% crystal violet. 5 random fields were counted per sample.

Histology Prior to paraffin embedding, mouse livers were fixed with 10% formalin and washed with 75% ethanol. Paraffin sections were dewaxed with xylene and rinsed with ethanol. Antigen retrieval was performed by boiling in EDTA buffer. Sections were stained with hematoxylin and eosin (H&E) or Ki67 (Abcam) antibody.

TCGA and Oncomine data Transcriptome sequencing data of 50 pairs of HCC and NT tissues were retrieved from The Cancer Genome Atlas (TCGA) via Broad Instituite (http://gdac.broadinstitute.org/). mRNA expression levels of the NDUFA4L2 in different cancer types were retrieved from Oncomine data base (https://www.oncomine.org/resource/login.html). Omnibus (GEO) accession numbers were provided in the supplementary figure for reference.

REFERENCES

1. Wong CC, Tse AP, Huang YP, Zhu YT, Chiu DK, Lai RK, et al. Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology. 2014;60:1645-58. 2. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, et al. Transcriptional regulation of vascular endothelial cell responses to by HIF-1. Blood. 2005;105:659-69. 3. Heigwer F, Kerr G, Walther N, Glaeser K, Pelz O, Breinig M, et al. E-TALEN: a web tool to design TALENs for genome engineering. Nucleic acids research. 2013;41:e190. 4. Sanjana NE, Cong L, Zhou Y, Cunniff MM, Feng G, Zhang F. A activator-like effector toolbox for genome engineering. Nature protocols. 2012;7:171-92.