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PubMed ID26861291
AuthorsCroner RS(1), Sevim M(2), Metodiev MV(3), Jo P(4), Ghadimi M(5), Schellerer V(6), Brunner M(7), Geppert C(8), Rau T(9), Stürzl M(10), Naschberger E(11), Matzel KE(12), Hohenberger W(13), Lottspeich F(14), Kellermann J(15).
TitleIdentification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis.
JournalInt J Mol Sci. 2016 Feb 4;17(2):209.
AbstractNeoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients' informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.

Sample characteristics

SpeciesTissue / SourceDiseaseNDetection methodSample
Homo sapiensrectumnCRT II, Dworak 1 + 2 (poor responder)20LTQ-hybrid mass spectrometerDem26861291b

Sample description and preparation

N (case)10
N (control)10
Disease (case)nCRT II, Dworak 1 + 2 (poor responder)
Disease (control)nCRT II, Dworak 3 + 4 (good responder)
Preparation specific methodlaser capture microdissection, Isotope Coded Protein Labeling (ICPL)
Digestin-solution digestion, Glu-C und Trypsin
Storage condition-80C

Sample analysis

Software analysis toolICPL-ESIQuant
Software thresholdP<0.05, fold change>1.5

Molecule list

Molecule IDextExternal IDGeneNameSource accRegulation (case/control)Scores
A0901 1433S_HUMANSFN, HME114-3-3 protein sigmaIPI00013890ratio: n.r.
A4547 ACTA_HUMANACTA2, ACTSA, ACTVSActin, aortic smooth muscleIPI00008603ratio: 0.58
A4548 ACTB_HUMANACTB, PS1TP5BP1Actin, cytoplasmic 1IPI00021439ratio: 0.57
A4549 ACTBL_HUMANACTBL2Beta-actin-like protein 2IPI00003269ratio: 0.52
A4551 ACTC_HUMANACTC1, ACTCActin, alpha cardiac muscle 1IPI00023006ratio: 0.29
A4552 ACTG_HUMANACTG1, ACTGActin, cytoplasmic 2IPI00021440ratio: 0.45
A2341 ACTN1_HUMANACTN1Alpha-actinin 1IPI00013508ratio: 0.52
A4555 ACTS_HUMANACTA1, ACTAActin, alpha skeletal muscleIPI00021428ratio: 0.19
A3599 AL1B1_HUMANALDH1B1, ALDH5, ALDHXAldehyde dehydrogenase X, mitochondrialIPI00103467ratio: 0.27
A3598 ALDH2_HUMANALDH2, ALDMAldehyde dehydrogenase, mitochondrial precursorIPI00006663ratio: 0.53
A1923 ALDOA_HUMANALDOA, ALDAFructose-bisphosphate aldolase AIPI00465439ratio: n.r.
A0537 ANXA2_HUMANANXA2, ANX2, ANX2L4Annexin A2IPI00418169ratio: 0.5
A8385 ANXA3_HUMANANXA3, ANX3Annexin A3IPI00024095ratio: n.r.
A4575 ANXA4_HUMANANXA4, PIG28, ANX4Annexin A4IPI00793199ratio: 0.58
A1552 APOA1_HUMANAPOA1, A175PApolipoprotein A-I precursorIPI00021841ratio: 1.78
A5817 APT_HUMANAPRTAdenine phosphoribosyltransferaseIPI00218693ratio: 2.02
A8681 ATIF1_HUMANATPIF1, ATPI, ASIATPase inhibitor, mitochondrial precursorIPI00553153ratio: n.r.
A5959 CAH1_HUMANCA1Carbonic anhydrase 1IPI00215983ratio: n.r.
A4633 CAP1_HUMANCAP1, CAPAdenylyl cyclase-associated protein 1IPI00008274ratio: n.r.
A0418 CAPZB_HUMANCAPZBCapping protein (actin filament) muscle Z-line, betaIPI00026185ratio: 0.58
A0418 CAPZB_HUMANCAPZBCapping protein (actin filament) muscle Z-line, betaIPI00218782ratio: n.r.
A4280 CH10_HUMANEPFP1, HSPE110 kDa heat shock protein, mitochondrialIPI00220362ratio: 0.49
A1628 CO9_HUMANC9Complement component C9 precursorIPI00022395ratio: n.r.
A2143 COR1A_HUMANCORO1A, CORO1Coronin-like protein p57IPI00010133ratio: n.r.
A3680 DHE3_HUMANGLUD1, GLUDGlutamate dehydrogenase 1, mitochondrial precursorIPI00016801ratio: 0.5
A4756 DSG2_HUMANDSG2, CDHF5Desmoglein 2 precursorIPI00028931ratio: n.r.
A3683 ECHA_HUMANHADHA, HADHTrifunctional enzyme alpha subunit, mitochondrial precursorIPI00031522ratio: 0.38
A4318 ERP44_HUMANERP44, TXNDC4, UNQ532/PRO1075Thioredoxin domain containing protein 4 precursorIPI00401264ratio: n.r.
A1542 FA7_HUMANF7Coagulation factor VII precursorIPI00382606ratio: 0.53
A0441 FABP5_HUMANFABP5Fatty acid binding protein 5 (psoriasis-associated)IPI00007797ratio: n.r.
A979B FABPL_HUMANFABP1, FABPLFatty acid-binding protein, liverIPI00010290ratio: 0.33
A1467 FIBA_HUMANFGAFibrinogen alpha/alpha-E chain precursorIPI00021885ratio: n.r.
A1467 FIBA_HUMANFGAFibrinogen alpha/alpha-E chain precursorIPI00029717ratio: n.r.
A1493 FIBB_HUMANFGBFibrinogen beta chain precursorIPI00298497ratio: n.r.
A1494 FIBG_HUMANFGG, PRO2061Fibrinogen gamma chain precursorIPI00021891ratio: n.r.
A1494 FIBG_HUMANFGG, PRO2061Fibrinogen gamma chain precursorIPI00219713ratio: n.r.
A1466 FINC_HUMANFN1, FNFibronectinIPI00022418ratio: n.r.
A4322 FKBP2_HUMANFKBP2, FKBP13FK506-binding protein 2 precursorIPI00002535ratio: 1.7
A0204 FLNA_HUMANFLNA, FLN, FLN1Filamin AIPI00302592ratio: 0.22
A4814 FLNB_HUMANFLNB, FLN3, TAPFilamin-BIPI00289334ratio: 0.39
A8804 GDIB_HUMANGDI2, RABGDIBRab GDP dissociation inhibitor betaIPI00031461ratio: n.r.
A1961 GSTP1_HUMANGSTP1, FAEES3, GST3Glutathione S-transferase PIPI00219757ratio: 1.85
A473A H15_HUMANHIST1H1B, H1F5Histone H1.5IPI00217468ratio: 2.16
A551A HNRH1_HUMANHNRPH1, HNRNPH1, HNRPHHeterogeneous nuclear ribonucleoprotein HIPI00013881ratio: n.r.
A557A HNRPF_HUMANHNRNPF, HNRPFHeterogeneous nuclear ribonucleoprotein FIPI00003881ratio: 2.26
A0717 HNRPK_HUMANHNRNPK, HNRPKHeterogeneous nuclear ribonucleoprotein KIPI00216049ratio: n.r.
A3792 HNRPM_HUMANHNRNPM, HNRPM, NAGR1Heterogeneous nuclear ribonucleoprotein MIPI00171903ratio: n.r.
A4856 HSPB1_HUMANHSPB1, HSP27, HSP28Heat shock protein beta-1IPI00025512ratio: 0.41
A3660 IDHP_HUMANIDH2, IDH, IDPIsocitrate dehydrogenase [NADP], mitochondrial precursorIPI00011107ratio: 0.23
A587A IF4H_HUMANEIF4H, WBSCR1, WSCR1Eukaryotic translation initiation factor 4HIPI00014263ratio: 1.85
A8269 IGHG2_HUMANIGHG2Ig gamma-2IPI00426051ratio: 2.35
A8269 IGHG2_HUMANIGHG2Ig gamma-2IPI00399007ratio: n.r.
A8270 IGHG3_HUMANIGHG3Ig gamma-3 chainIPI00168728ratio: n.r.
A8270 IGHG3_HUMANIGHG3Ig gamma-3 chainIPI00876888ratio: 0.2
A8271 IGHG4_HUMANIGHG4Ig gamma-4 chainIPI00550640ratio: n.r.
A8420 ILEU_HUMANSERPINB1, ELANH2, MNEILeukocyte elastase inhibitorIPI00027444ratio: 0.49
A6871 KPYM_HUMANPKM2, OIP3, PK2Pyruvate kinase, M1 isozymeIPI00479186ratio: 0.43
A6871 KPYM_HUMANPKM2, OIP3, PK2Pyruvate kinase, M1 isozymeIPI00220644ratio: n.r.
A639A LEG3_HUMANLGALS3, MAC2, GALIGGalectin-3IPI00465431ratio: n.r.
A0430 LMNB1_HUMANLMNB1, LMN2, LMNBLamin B1IPI00217975ratio: 0.47
A4951 LUM_HUMANLUM, LDC, SLRR2DLumican precursorIPI00020986ratio: n.r.
A3696 MDHM_HUMANMDH2Malate dehydrogenase, mitochondrial precursorIPI00291006ratio: 0.46
A2268 MFAP4_HUMANMFAP4Microfibril-associated glycoprotein 4 precursorIPI00022792ratio: 0.09
A156C MVP_HUMANMVP, LRPMajor vault proteinIPI00000105ratio: n.r.
A2331 MYH11_HUMANMYH11, SMMHCMyosin heavy chain, smooth muscle isoformIPI00024870ratio: 0.5
A2331 MYH11_HUMANMYH11, SMMHCMyosin heavy chain, smooth muscle isoformIPI00020501ratio: 0.43
A3962 MYH14_HUMANMYH14, FP17425Myosin-14IPI00337335ratio: 0.57
A3166 MYH9_HUMANMYH9Myosin heavy chain 9, non-muscleIPI00019502ratio: 0.4
A4049 MYL6_HUMANMYL6, MLC3nm, LC17AMyosin light polypeptide 6IPI00335168ratio: 0.49
A8930 MZB1_HUMANMZB1, PACAP, HSPC190Plasma cell-induced resident endoplasmic reticulum proteinIPI00102821ratio: 2.58
A224C NGAL_HUMANLCN2, HNL, NGALNeutrophil gelatinase-associated lipocalin precursorIPI00299547ratio: 1.9
A0607 PA2G4_HUMANPA2G4, EBP1, P38-2G4Proliferation-associated protein 2G4IPI00299000ratio: n.r.
A825A PAIRB_HUMANSERBP1, PAIRBP1, CGI-55PAI-1 mRNA-binding proteinIPI00410693ratio: n.r.
A825A PAIRB_HUMANSERBP1, PAIRBP1, CGI-55PAI-1 mRNA-binding proteinIPI00412714ratio: 1.68.
A825A PAIRB_HUMANSERBP1, PAIRBP1, CGI-55PAI-1 mRNA-binding proteinIPI00470498ratio: 1.71
A1816 PDIA3_HUMANPDIA3, ERP57, ERP60Protein disulfide isomerase A3 precursorIPI00025252ratio: n.r.
A7372 PGK1_HUMANPGK1, PGKA, MIG10Phosphoglycerate kinase 1IPI00169383ratio: n.r.
A3464 PGRC1_HUMANPGRMC1, HPR6.6, PGRMCMembrane associated progesterone receptor component 1IPI00220739ratio: n.r.
A5077 PGS1_HUMANBGN, SLRR1ABiglycan precursorIPI00010790ratio: n.r.
A1322 PIGR_HUMANPIGRPolymeric immunoglobulin receptor precursorIPI00004573ratio: 1.78
A1941 PLEC_HUMANPLEC1, PLECPlectinIPI00014898ratio: 0.43
A4369 PPIA_HUMANPPIA, CYPAPeptidyl-prolyl cis-trans isomerase AIPI00419585ratio: n.r.
A0371 PRDX1_HUMANPRDX1, PAGA, PAGBPeroxiredoxin 1IPI00000874ratio: n.r.
A0372 PRDX2_HUMANPRDX2, NKEFB, TDPX1Peroxiredoxin 2IPI00027350ratio: 0.49
A7502 PRDX4_HUMANPRDX4Peroxiredoxin 4IPI00011937ratio: n.r.
A3676 QCR1_HUMANUQCRC1Ubiquinol-cytochrome C reductase complex core protein I, mitochondrial precursorIPI00013847ratio: 0.52
A0368 RL13A_HUMANRPL13A, RPL13a60S ribosomal protein L13aIPI00304612ratio: 1.83
A9548 RL22_HUMANRPL22, RPL22L260S ribosomal protein L22IPI00219153ratio: n.r.
A3639 RPN1_HUMANRPN1Dolichyl-diphosphooligosaccharide-protein glycosyltransferase 67 kDa subunit precursorIPI00025874ratio: n.r.
A3817 RS3A_HUMANRPS3A, FTE1, MFTL40S ribosomal protein S3AIPI00419880ratio: n.r.
A276E S10A4_HUMANS100A4, CAPL, MTS1Placental calcium-binding proteinIPI00032313ratio: 0.23
A0536 S10A6_HUMANS100A6, CACYCalcyclinIPI00027463ratio: n.r.
A1597 SAMP_HUMANAPCS, PTX2Serum amyloid P-component precursorIPI00022391ratio: n.r.
A5127 SHRM4_HUMANSHROOM4, SHAPProtein SHROOM4IPI00008176ratio: 0.53
A5161 STMN1_HUMANSTMN1, LAP18, OP18StathminIPI00479997ratio: 1.65
A7900 SUCB2_HUMANSUCLG2Succinyl-CoA ligase [GDP-forming] beta-chain, mitochondrial precursorIPI00096066ratio: 0.46
A5174 TAGL_HUMANTAGLN, SM22, WS3-10TransgelinIPI00216138ratio: 0.28
A5178 TBA1A_HUMANTUBA1A, TUBA3Tubulin alpha-1A chainIPI00180675ratio: n.r.
A5180 TBA1C_HUMANTUBA1C, TUBA6Tubulin alpha-1C chainIPI00218343ratio: 2.1
A5183 TBA4A_HUMANTUBA4A, TUBA1, TUBA4Tubulin alpha-4A chainIPI00007750ratio: n.r.
A5192 TBB3_HUMANTUBB3, TUBB4Tubulin beta-3 chainTubulin beta-4 chainIPI00013683ratio: n.r.
A5193 TBB4A_HUMANTUBB4, TUBB4A, TUBB5Tubulin beta-4 chainIPI00011654ratio: n.r.
A5191 TBB4B_HUMANTUBB2C, TUBB4B, TUBB2Tubulin beta-2 chainIPI00007752ratio: n.r.
A3540 TCPB_HUMANCCT2, 99D8.1, CCTBT-complex protein 1, beta subunitIPI00297779ratio: n.r.
A1525 TENA_HUMANTNC, HXBTenascin precursorIPI00031008ratio: n.r.
A7979 THIM_HUMANACAA2Acetyl-CoA acyltransferase 2IPI00001539ratio: 0.48
A7989 TKT_HUMANTKT, TKT1TransketolaseIPI00643920ratio: 0.47
A3965 TPM1_HUMANTPM1, TMSATropomyosin 1 alpha chainIPI00216134ratio: n.r.
A3965 TPM1_HUMANTPM1, TMSATropomyosin 1 alpha chainIPI00000230ratio: 0.47
A3965 TPM1_HUMANTPM1, TMSATropomyosin 1 alpha chainIPI00018853ratio: 0.54
A3965 TPM1_HUMANTPM1, TMSATropomyosin 1 alpha chainIPI00216135ratio: 0.51
A3965 TPM1_HUMANTPM1, TMSATropomyosin 1 alpha chainIPI00604537ratio: 0.47
A5222 TPM2_HUMANTPM2, TMSB, TPM2bTropomyosin beta chainIPI00218820ratio: 0.52
A5222 TPM2_HUMANTPM2, TMSB, TPM2bTropomyosin beta chainIPI00220709ratio: 0.51
A5222 TPM2_HUMANTPM2, TMSB, TPM2bTropomyosin beta chainIPI00843757ratio: 0.19
A3205 TPM3_HUMANTPM3Tropomyosin alpha 3 chainIPI00183968ratio: 0.3
A3205 TPM3_HUMANTPM3Tropomyosin alpha 3 chainIPI00218319ratio: 0.56
A5224 TPM4_HUMANTPM4Tropomyosin alpha 4 chainIPI00010779ratio: 0.3
A1712 TRFL_HUMANLTF, LF, GIG12Lactotransferrin precursorIPI00298860ratio: 0.41
A1292 UBE2N_HUMANUBE2N, BLUUbiquitin-conjugating enzyme E2 NIPI00003949ratio: 1.51
A0425 VDAC1_HUMANVDAC1, VDAC, VDAC4Voltage-dependent anion-selective channel protein 1IPI00216308ratio: 0.45
A0426 VDAC2_HUMANVDAC2Voltage-dependent anion-selective channel protein 2IPI00024145ratio: 0.46
A5242 VILI_HUMANVIL1, VILVillin 1IPI00218852ratio: n.r.
A5250 WDR1_HUMANWDR1, PNAS-29WD-repeat containing protein 1IPI00216256ratio: 0.56
A1939 HV102_HUMANIGH, VH1, IGHG1Immunoglobulin G1 Fab heavy chain variable regionIPI00815926ratio: 0.47
A8363 IGHM_HUMANIGHM, IgIg mu chain CIPI00549291ratio: 0.24
A8273 KV402_HUMANIGK, SDNK1, A30Ig kappa chainIPI00472961ratio: n.r.
A8273 KV402_HUMANIGK, SDNK1, A30Ig kappa chainIPI00736885ratio: 0.34
A8273 KV402_HUMANIGK, SDNK1, A30Ig kappa chainIPI00743194ratio: 0.34
A8273 KV402_HUMANIGK, SDNK1, A30Ig kappa chainIPI00746963ratio: 0.43
A4629 CALD1_HUMANCALD1, CAD, CDMCaldesmonIPI00014516ratio: n.r.
A4629 CALD1_HUMANCALD1, CAD, CDMCaldesmonIPI00218695ratio: n.r.
A4629 CALD1_HUMANCALD1, CAD, CDMCaldesmonIPI00333771ratio: 0.55
A0567 GDIA_HUMANGDI1, GDIL, OPHN2Rab GDP dissociation inhibitor alphaIPI00010154ratio: n.r.
A5094 POTEI_HUMANPOTEI, P704P, ACTPOTE ankyrin domain family member IIPI00555733ratio: 0.61
A7501 PRDX3_HUMANPRDX3, mer5, AOP1Thioredoxin-dependent peroxide reductase, mitochondrial precursorIPI00024919ratio: 0.53

Compile date 10-20-2017© .