Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro

  • Authors:
    • I-Tsang Chiang
    • Wei-Shu Wang
    • Hsin-Chung Liu
    • Su-Tso Yang
    • Nou-Ying Tang
    • Jing-Gung Chung
  • View Affiliations

  • Published online on: July 29, 2015     https://doi.org/10.3892/or.2015.4159
  • Pages: 1853-1874
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Abstract

Lung cancer is the most common cause of cancer mortality and new cases are on the increase worldwide. However, the treatment of lung cancer remains unsatisfactory. Curcumin has been shown to induce cell death in many human cancer cells, including human lung cancer cells. However, the effects of curcumin on genetic mechanisms associated with these actions remain unclear. Curcumin (2 µM) was added to NCI-H460 human lung cancer cells and the cells were incubated for 24 h. Total RNA was extracted from isolated cells for cDNA synthesis, labeling, microarray hybridization and flour‑labeled cDNA hybridized on chip. Localized concentrations of fluorescent molecules were detected and quantified using Expression Console software (Affymetrix) with default RMA parameters. GeneGo software was used for the key genes involved and their possible interaction pathways. The results showed that ~170 genes were significantly upregulated and 577 genes were significantly downregulated in curcumin‑treated cells. Specifically, the up‑ and downregulated genes included CCNE2, associated with DNA damage; ID3, associated with cell survival and 146 genes with a >2- to 3-fold change including the TP53INP1 gene, associated with DNA damage; CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L, associated with cell migration and invasion. Additionally, 59 downregulated genes exhibited a >4-fold change, including the DDIT3 gene, associated with DNA damage; while 97 genes had a >3- to 4-fold change including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with cell cycle and 321 genes with a >2- to 3-fold including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with cell cycle, the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B gene, associated with cell survival and the ARHAP29 and CADM2 genes, associated with cell migration and invasion. In conclusion, gene alterations provide information regarding the cytotoxic mechanism of curcumin at the genetic level and provide additional biomarkers or targets for the treatment of human lung cancer.

Introduction

Lung cancer, a leading cause of cancer-associated mortality wordwide, is one of the most aggressive human cancers and almost 80% of lung cancer-related deaths are non-small-cell lung cancer (NSCLC) (1,2). Despite recent improvements in chemotherapy and molecular-targeted therapy in lung cancer patients, the outcome of lung cancer remains poor. Treatments can also cause serious side effects that affect quality of life of patients (3). Although there has been considerable progress in the diagnosis and treatment of lung cancer, the overall 5-year survival rate of NSCLC patients remains <15% (4). Thus, studies have focused on new anticancer drugs derived from natural products and attempted to improve the disadvantage of the treatment of lung cancer.

Curcumin, a component of turmeric, is derived from the rhizome of Curcuma longa. Previous findings have shown that curcumin has anticancer activities for various types of cancer in vitro and in vivo (5). Curcumin has been found to interfere with pathways that are overexpressed in cancer cells, such as NFκB, STAT3 and PI3K/Akt to induce cell death in tumors (6). Curcumin also acts as a chemoprotective agent (79). Intraperitoneally administered curcumin in rats was able to decrease brain-implanted glioblastomas in vivo (10). Additionally, curcumin induces autophagy by activating the AMPK signaling pathway in human lung adenocarcinoma cells (11). Curcumin inhibits migration and invasion of human lung cancer cells through inhibition of the Rac1/PAK1 signaling pathway and MMP-2 and MMP-9 (12). Recently, it was reported that curcumin significantly reduced the tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice (13).

Cells maintain normal functions and survival via genome integrity. However, genome instability of cells causes genetic aberrations and is considered a hallmark of most types of cancer (14). After the presence of DNA damage, p53 protein can be activated to promote important gene expressions that are involved in cell cycle arrest, DNA repair and apoptosis (15). Thus, identification of genetic abnormalities in NSCLC has been used for the development of targeted therapeutic approaches in NSCLC treatment. Targeting tumors carrying mutations in EGFR or a fusion of the EML4 and ALK genes used clinically have been successful as first-line therapies in NSCLC (1618). Therefore, it is imperative to identify gene expression or inhibition in NSCLC affected by test compounds or drugs to investigate the molecular mechanism to determine the function of these agents. Although curcumin has been demonstrated to induce cytotoxic effects on many human cancer cells, how associated total genes in human lung cancer cells (NSCLC) are affected by curcumin remains to be determined. Thus, we used cDNA microarray to investigate the altered gene expression in NCI-H460 cells following exposure to curcumin and the results indicated that curcumin altered certain gene expression associated with apoptosis.

Materials and methods

Chemicals and reagents

Curcumin and dimethylsulfoxide (DMSO) were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Culture medium RPMI-1640, fetal bovine serum (FBS), 1% L-glutamine, 100 U/ml penicillin and 100 µg/ml streptomycin were obtained from Gibco-BRL (Grand Island, NY, USA). Curcumin was dissolved in DMSO and stored at −20°C prior to use.

Lung cancer cells

The NCI-H460 human NSCLC cell line was purchased from the Food Industry Research and Development Institute (Hsinchu, Taiwan). The cells were cultured in RPMI-1640 medium and supplemented with 10% FBS, 1% L-glutamine and 1% penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA) at 37°C in a humidified atmosphere of 95% air and 5% CO2 air. The cells were split every 4 days to maintain exponential growth and were harvested with 0.025% trypsin and 0.52 mM EDTA in phosphate-buffered saline (PBS), plated at required cell numbers and allowed to adhere for ~24 h prior to treatment.

cDNA microarray assay used for gene expression in NCI-H460 cells following exposure to curcumin

NCI-H460 cells (5×105 cells/ml) were kept in 12-well plates with RPMI-1640 medium for 24 h and then incubated with or without 2 µM of curcumin for 24 h. After treatment, the cells were collected and total RNA from each sample was extracted using a Qiagen RNeasy Mini kit (Qiagen Inc., Valencia, CA, USA) as previously described (19). Total RNA from curcumin-treated and -untreated cells was quantified and used for cDNA synthesis, labeling and microarray hybridization, followed by flour-labeled cDNA hybridizing their complements on the chip (Affymetrix GeneChip Human Gene 1.0 ST array; Affymetrix, Santa Clara, CA, USA) as previously described (19). On the chip, the resulting localized concentrations of fluorescent molecules were detected and quantified (Asia BioInnovations Corporation, Taipei, Taiwan) and data were further analyzed using Expression Console software (Affymetrix) with default RMA parameters (19,20). Up- or downregulated gene expressions was affected by DMC in NCI-H460 cells and a ≥2-fold change was recorded and identified. Data were representative of three independent assays.

Statistical analysis

The results were representative of three assays. Differences between curcumin-treated and -untreated groups were presented up to 2-fold changes, with + signifying upregulation and −, downregulation.

Results

Curcumin induces the up- and downregulated gene expression in NCI-H460 cells

The NCI-H460 cells were incubated with or without 2 µM of curcumin and collected to extract total RNA. The cells were then used for cDNA microarray analysis and results are shown in Tables I and II. Table I indicated that 4 genes exhibited >4-fold change, 20 genes were >3- to 4-fold including the CCNE2 gene, associated with DNA damage; the ID3 gene, associated with cell survival and 146 genes exhibited a >2- to 3-fold change, including the TP53INP1 gene, associated with DNA damage; the CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2 gene, associated with the cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L gene, associated with cell migration and invasion.

Table I

Representative genes of NCI-H460 cells upregulated following curcumin treatment.

Table I

Representative genes of NCI-H460 cells upregulated following curcumin treatment.

Fold-changeGene symbolmRNA description
5.64LOC100506948Uncharacterized LOC100506948; small nucleolar RNA, C/D box 116-28; 115-26; 115-13; 115-7; 115-9; 115-11; 115-12; 115-29; 115-36; 115-39; 115-43
4.57CYP1A1Cytochrome P450, family 1, subfamily A
4.46TIPARPTCDD-inducible poly(ADP-ribose) polymerase
4.03NAP1L2Nucleosome assembly protein 1-like 2
3.98METTL7B Methyltransferase-like 7B
3.79CCNE2Cyclin E2
3.74DLX2Distal-less homeobox 2
3.69TRNAK37PTransfer RNA lysine 37 (anticodon CUU) pseudogene
3.62POLR2APolymerase (RNA) II (DNA directed) polypeptide A, 220 kDa
3.56ID3Inhibitor of DNA binding 3, dominant-negative
3.49RN5S452RNA, 5S ribosomal 452
3.44SNRPNUncharacterized LOC100506948; small nucleolar RNA, C/D box 116-28; 115-26; 115-13; 115-7; 115-5; 115-9; 115-11; 115-12; 115-29
3.40SNORD115-4Small nucleolar RNA, C/D box 115-4; 115-6; 115-42
3.34RNU1-13PRNA, U1 small nuclear 12, 13, pseudogene
3.29CLSPNClaspin
3.26SNORD115-5Small nucleolar RNA, C/D box 115-5; 115-12; 115-9; 115-43; 115-36; 115-29; 115-11; 115-20
3.20GUCY1B3Guanylate cyclase 1, soluble, β3
3.20HSPA1AHeat shock 70 kDa protein 1A; 1B
3.19SNORD115-6Small nucleolar RNA, C/D box 115-6; 115-42
3.15SFNStratifin
3.09TUBB2ATubulin, β2A class IIa
3.05RNY4P15RNA, Ro-associated Y4 pseudogene 15
3.03FLJ44896FLJ44896 protein
3.02PIK3R3 Phosphoinositide-3-kinase, regulatory subunit 3 (γ)
2.99CARD6Caspase recruitment domain family, member 6
2.99TRNAU2Transfer RNA selenocysteine 2 (anticodon UCA)
2.96FOSBFBJ murine osteosarcoma viral oncogene homolog B
2.94RNU1-10PRNA, U1 small nuclear 10, pseudogene
2.93SAMD15Sterile α motif domain containing 15
2.91FGD6FYVE, RhoGEF and PH domain containing 6
2.87NAV1Neuron navigator 1
2.85FAM171BFamily with sequence similarity 171, member B
2.82VDRVitamin D (1,25-dihydroxyvitamin D3) receptor
2.81ORC1Origin recognition complex, subunit 1
2.81DNAH14Dynein, axonemal, heavy chain 14
2.77SNORD115-44Small nucleolar RNA, C/D box 115-44
2.77GLULP4Glutamate-ammonia ligase (glutamine synthetase) pseudogene 4
2.76LPCAT2 Lysophosphatidylcholine acyltransferase 2
2.75GTF2IGeneral transcription factor IIi
2.70ID1Inhibitor of DNA binding 1, dominant-negative helix-loop-helix protein
2.67HSPH1Heat shock 105/110 kDa protein 1
2.58HIST1H3AHistone cluster 1, H3a; H3f; H3b; H3h; H3j; H3g; H3i; H3e; H3c; H3d
2.57STOX1Storkhead box 1
2.57RN5S183RNA, 5S ribosomal 183
2.56CROTCarnitine O-octanoyltransferase
2.56CDC6Cell division cycle 6 homolog (S. cerevisiae)
2.55IFIT3Interferon-induced protein with tetratricopeptide repeats 3
2.54FOSFBJ murine osteosarcoma viral oncogene homolog
2.52SLC29A3Solute carrier family 29 (nucleoside transporters), member 3
2.51PKI55DKFZp434H1419
2.49HMGCS1 3-Hydroxy-3-methylglutaryl-CoA synthase 1 (soluble)
2.45TACC1Transforming, acidic coiled-coil containing protein 1
2.45DHFRDihydrofolate reductase
2.44ZNF480Zinc finger protein 480
2.40KIF5CKinesin family member 5C
2.39DNAJA1DnaJ (Hsp40) homolog, subfamily A, member 1
2.38PPP2R3AProtein phosphatase 2, regulatory subunit B', α
2.37HMGN3P1High mobility group nucleosomal binding domain 3 pseudogene 1
2.37EML1Echinoderm microtubule-associated protein like 1
2.33SRRTSerrate RNA effector molecule homolog (Arabidopsis)
2.32DBR1Debranching enzyme homolog 1 (S. cerevisiae)
2.31JAKMIP2Janus kinase and microtubule interacting protein 2
2.31CASC5Cancer susceptibility candidate 5
2.30MFSD5Major facilitator superfamily domain containing 5
2.30MCM4Minichromosome maintenance complex component 4
2.29NEFLNeurofilament, light polypeptide
2.29SGK3 Serum/glucocorticoid-regulated kinase family, member 3; C8orf44-SGK3 readthrough
2.28NCOA5Nuclear receptor coactivator 5
2.27MSRB1Methionine sulfoxide reductase B1
2.27BRMS1LBreast cancer metastasis-suppressor 1-like
2.26NRG4Neuregulin 4
2.26LOC100653168Formin-1-like; formin 1
2.26CDCA5Cell division cycle-associated 5
2.26GINS3GINS complex subunit 3 (Psf3 homolog)
2.25LOC100653119Coiled-coil and C2 domain-containing protein 2A-like; coiled-coil and C2 domain containing 2B
2.25LPHN2Latrophilin 2
2.25KIF20AKinesin family member 20A
2.25TMEM14ATransmembrane protein 14A
2.25HERC5HECT and RLD domain containing E3 ubiquitin protein ligase 5
2.25TUBB4BTubulin, β4B class IVb
2.25ANLNAnillin, actin binding protein
2.24CKS2CDC28 protein kinase regulatory subunit 2
2.23TSPYL2TSPY-like 2
2.23RPA2Replication protein A2, 32 kDa
2.22RNF38Ring finger protein 38
2.22RFWD3Ring finger and WD repeat domain 3
2.21GRK5G protein-coupled receptor kinase 5
2.21ZNF107Zinc finger protein 107
2.21SKA3Spindle and kinetochore-associated complex subunit 3
2.21NAGKN-acetylglucosamine kinase
2.21CTR9Ctr9, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)
2.19DIO2Deiodinase, iodothyronine, type II
2.19AHSA1AHA1, activator of heat shock 90 kDa protein ATPase homolog 1 (yeast)
2.19C3orf14Chromosome 3 open reading frame 14
2.18MARCH8Membrane-associated ring finger (C3HC4) 8, E3 ubiquitin protein ligase
2.18LPAL2Lipoprotein, Lp(a)-like 2, pseudogene
2.18TUBB4BTubulin, β4B class IVb
2.17GATA2GATA binding protein 2
2.17PAR4 Prader-Willi/Angelman region gene 4; small nucleolar RNA, C/D box 115-23
2.17TRIP13Thyroid hormone receptor interactor 13
2.17MAPRE2 Microtubule-associated protein, RP/EB family, member 2
2.16CHST11Carbohydrate (chondroitin 4) sulfotransferase 11
2.16SAMD9Sterile α motif domain containing 9
2.16MT1XMetallothionein 1X
2.16FNIP2 Folliculin-interacting protein 2
2.16TACC3Transforming, acidic coiled-coil containing protein 3
2.15TERF1P2Telomeric repeat binding factor (NIMA-interacting) 1 pseudogene 2
2.15ZNF611Zinc finger protein 611
2.14C9orf78Chromosome 9 open reading frame 78
2.14DHX9DEAH (Asp-Glu-Ala-His) box polypeptide 9
2.13DHFRDihydrofolate reductase; dihydrofolate reductase pseudogene
2.13TMEM171Transmembrane protein 171
2.12ID2Inhibitor of DNA binding 2, dominant negative helix-loop-helix protein
2.12CDK14Cyclin-dependent kinase 14
2.12TRNASUP1Transfer RNA suppressor 1 (anticodon UUA)
2.11SMAD9SMAD family member 9
2.11MCM2Minichromosome maintenance complex component 2
2.11CT45A5Cancer/testis antigen family 45, member A5; A2; A3; A4 cancer/testis antigen family 45, member A1; A6
2.11GDAP1Ganglioside induced differentiation associated protein 1
2.11MCM10Minichromosome maintenance complex component 10
2.11CABLES1Cdk5 and Abl enzyme substrate 1
2.11CENPQCentromere protein Q
2.11CKAP2Cytoskeleton associated protein 2
2.11FAM19A1Family with sequence similarity 19 [chemokine (C-C motif)-like], member A1
2.11MEPCEMethylphosphate capping enzyme
2.11REEP1Receptor accessory protein 1
2.10SNORD115-32Small nucleolar RNA, C/D box 115-32
2.10ATP6V0D1ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d1
2.10WDR6WD repeat domain 6
2.10SNX10Sorting nexin 10
2.10BRPF3Bromodomain and PHD finger containing, 3
2.10FAM217BFamily with sequence similarity 217, member B
2.10EML6Echinoderm microtubule-associated protein-like 6
2.10SAFB2Scaffold attachment factor B2
2.09TP53INP1Tumor protein p53 inducible nuclear protein 1
2.09CPMCarboxypeptidase M
2.09CDRT1CMT1A duplicated region transcript 1
2.09CDCA7LCell division cycle associated 7-like
2.08SMAD6SMAD family member 6
2.10SAFB2Scaffold attachment factor B2
2.09TP53INP1Tumor protein p53 inducible nuclear protein 1
2.09CPMCarboxypeptidase M
2.09CDRT1CMT1A duplicated region transcript 1
2.09CDCA7LCell division cycle associated 7-like
2.08SMAD6SMAD family member 6
2.08CCDC138Coiled-coil domain containing 138
2.07TUBB2ATubulin, β2A class IIa; tubulin, β2B class IIb
2.07FEN1Flap structure-specific endonuclease 1
2.06CYP1B1Cytochrome P450, family 1, subfamily B, polypeptide 1
2.06CDC25ACell division cycle 25 homolog A (S. pombe)
2.05WNK3WNK lysine deficient protein kinase 3
2.05CXorf26Chromosome X open reading frame 26
2.04TATDN2TatD DNase domain containing 2
2.04ZNF840Zinc finger protein 840
2.04EIF4EBP2Eukaryotic translation initiation factor 4E binding protein 2
2.04PCYT2Phosphate cytidylyltransferase 2, ethanolamine
2.03DUSP2Dual specificity phosphatase 2
2.03CEP19Centrosomal protein 19 kDa
2.03HMGN2High mobility group nucleosomal binding domain 2
2.02DNAH6Dynein, axonemal, heavy chain 6
2.02DYNLL1Dynein, light chain, LC8-type 1
2.02NAT1N-acetyltransferase 1 (arylamine N-acetyltransferase)
2.02PPP2R5DProtein phosphatase 2, regulatory subunit B', δ
2.02DPYSL3 Dihydropyrimidinase-like 3
2.02PCYT2Phosphate cytidylyltransferase 2, ethanolamine
2.02SHCBP1SHC SH2-domain binding protein 1
2.02CDC5LCDC5 cell division cycle 5-like (S. pombe)
2.02CDKN2CCyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4)
2.02FRMD3FERM domain containing 3
2.02SKP2S-phase kinase-associated protein 2, E3 ubiquitin protein ligase
2.01TRNAP28PTransfer RNA proline 28 (anticodon AGG) pseudogene
2.01LOC100129648Uncharacterized LOC100129648
2.01NXF1Nuclear RNA export factor 1
2.01ADI1Acireductone dioxygenase 1
2.01CFBComplement factor B
2.01ZNF483Zinc finger protein 483

Table II

Representative genes of NCI-H460 cells those were upregulated by curcumin treatment.

Table II

Representative genes of NCI-H460 cells those were upregulated by curcumin treatment.

Fold-changeGene symbolmRNA description
−2.01HORMAD1HORMA domain containing 1
−2.01EGFREpidermal growth factor receptor
−2.01VTNVitronectin; SEBOX homeobox
−2.01PGAP1Post-GPI attachment to proteins 1
−2.01ZAKSterile α motif and leucine zipper containing kinase AZK
−2.01PLOD1Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1
−2.01HPCAL1Hippocalcin-like 1
−2.01ALS2CR8Amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 8
−2.01RPS6KA2Ribosomal protein S6 kinase, 90 kDa, polypeptide 2
−2.01ITPR3Inositol 1,4,5-trisphosphate receptor, type 3
−2.01LEPRE1Leucine proline-enriched proteoglycan (leprecan) 1
−2.01FJX1Four jointed box 1 (Drosophila)
−2.02GALC Galactosylceramidase
−2.02TNFRSF11BTumor necrosis factor receptor superfamily, member 11b
−2.02DENND3DENN/MADD domain containing 3
−2.02SORT1Sortilin 1
−2.02IGFBP7Insulin-like growth factor binding protein 7
−2.02IGF2BP2Insulin-like growth factor 2 mRNA binding protein 2
−2.02TAS2R31Taste receptor, type 2, member 31; taste receptor, type 2, member 45
−2.02LMBRD2LMBR1 domain containing 2
−2.02SNORD77Small nucleolar RNA, C/D box 77
−2.02C6orf120Chromosome 6 open reading frame 120
−2.02FAM188AFamily with sequence similarity 188, member A
−2.02RBCK1RanBP-type and C3HC4-type zinc finger containing 1
−2.02FHDC1FH2 domain containing 1
−2.03DYNC1H1Dynein, cytoplasmic 1, heavy chain 1
−2.03ANKHAnkylosis, progressive homolog (mouse)
−2.03TSSC1Tumor-suppressing subtransferable candidate 1
−2.03CLYBLCitrate lyase β-like
−2.03GAS5Growth arrest-specific 5 (non-protein coding); small nucleolar RNA, C/D box 80
−2.03CEBPGCCAAT/enhancer binding protein (C/EBP), γ
−2.04BCKDHABranched chain keto acid dehydrogenase E1, α polypeptide
−2.04CCNB1IP1Cyclin B1 interacting protein 1, E3 ubiquitin protein ligase
−2.04TMEM67Transmembrane protein 67
−2.02RBCK1RanBP-type and C3HC4-type zinc finger containing 1
−2.02FAM27E3Family with sequence similarity 27, member E3; E2
−2.02FHDC1FH2 domain containing 1
−2.03DYNC1H1Dynein, cytoplasmic 1, heavy chain 1
−2.03SNORD49BSmall nucleolar RNA, C/D box 49B; box 65; C17orf76 antisense RNA 1 (non-protein coding); small nucleolar RNA, C/D box 49A
−2.03ANKHAnkylosis, progressive homolog (mouse)
−2.03TSSC1Tumor-suppressing subtransferable candidate 1
−2.03CLYBLCitrate lyase β-like
−2.03GAS5Growth arrest-specific 5 (non-protein coding); small nucleolar RNA, C/D box 80
−2.02FHDC1FH2 domain containing 1
−2.03DYNC1H1Dynein, cytoplasmic 1, heavy chain 1
−2.03SNORD49BSmall nucleolar RNA, C/D box 49B; 65; C17orf76 antisense RNA 1 (non-protein coding); small nucleolar RNA, C/D box 49A
−2.03TSSC1Tumor-suppressing subtransferable candidate 1
−2.03CLYBLCitrate lyase β-like
−2.03GAS5Growth arrest-specific 5 (non-protein coding); small nucleolar RNA, C/D box 80
−2.03CEBPGCCAAT/enhancer binding protein (C/EBP), γ
−2.04BCKDHABranched chain keto acid dehydrogenase E1, α polypeptide
−2.04CCNB1IP1Cyclin B1 interacting protein 1, E3 ubiquitin protein ligase
−2.04LCN1Lipocalin 1
−2.04TMEM67Transmembrane protein 67
−2.04PLD3Phospholipase D family, member 3
−2.04FAM27E3Family with sequence similarity 27, member E3; family with sequence similarity 27, member E2
−2.04ABCA2ATP-binding cassette, sub-family A (ABC1), member 2
−2.05PBX1Pre-B-cell leukemia homeobox 1
−2.05C11orf54Chromosome 11 open reading frame 54
−2.05KRTAP5-5Keratin-associated protein 5-5
−2.05RAP2BRAP2B, member of RAS oncogene family
2.05PLK2Polo-like kinase 2
−2.05SLC9A3Solute carrier family 9, subfamily A (NHE3, cation proton antiporter 3), member 3
−2.05ARSGArylsulfatase G
−2.06CADM2Cell adhesion molecule 2
−2.06SCDStearoyl-CoA desaturase (δ-9-desaturase)
2.05PLK2Polo-like kinase 2
−2.05SLC9A3Solute carrier family 9, subfamily A (NHE3, cation proton antiporter 3), member 3
−2.05ARSGArylsulfatase G
−2.06CADM2Cell adhesion molecule 2
−2.06SLPISecretory leukocyte peptidase inhibitor
−2.06RND3Rho family GTPase 3
−2.06CD9CD9 molecule; uncharacterized LOC100653288
−2.06PLOD2Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2
−2.06GPC6Glypican 6
−2.06RASSF8Ras association (RalGDS/AF-6) domain family (N-terminal) member 8
−2.06MESTMesoderm-specific transcript homolog (mouse)
−2.06SIAESialic acid acetylesterase
−2.06CSGALNACT2Chondroitin sulfate N-acetylgalactosaminyltransferase 2
−2.06JHDM1DJumonji C domain containing histone demethylase 1 homolog D (S. cerevisiae)
−2.06ASAH1N-acylsphingosine amidohydrolase (acid ceramidase) 1
−2.07P2RX4Purinergic receptor P2X, ligand-gated ion channel, 4
−2.07RBM24RNA binding motif protein 24
−2.07GPR108G protein-coupled receptor 108
−2.07ACTR1BARP1 actin-related protein 1 homolog B, centractin β (yeast)
−2.07CTPS1CTP synthase 1
−2.07RNF41Ring finger protein 41
−2.07SLC1A4Solute carrier family 1 (glutamate/neutral amino acid transporter), member 4
−2.08BCHE Butyrylcholinesterase
−2.08GPT2Glutamic pyruvate transaminase (alanine aminotransferase) 2
−2.08COL12A1Collagen, type XII, α1
−2.08ARG2Arginase, type II
−2.08HFM1HFM1, ATP-dependent DNA helicase homolog (S. cerevisiae)
−2.08NOX1NADPH oxidase 1
−2.08SNX14Sorting nexin 14
−2.08CD109CD109 molecule
−2.09CNTNAP3 Contactin-associated protein-like 3; contactin-associated protein-like 3B
−2.09MCL1Myeloid cell leukemia sequence 1 (BCL2-related)
−2.09L1CAML1 cell adhesion molecule
−2.09PART1Prostate androgen-regulated transcript 1 (non-protein coding)
−2.09TCF4Transcription factor 4
−2.09IGF1RInsulin-like growth factor 1 receptor
−2.09LRP12Low-density lipoprotein receptor-related protein 12
−2.09SLC50A1Solute carrier family 50 (sugar transporter), member 1
−2.09GLDNGliomedin
−2.10CYFIP2Cytoplasmic FMR1 interacting protein 2
−2.10SNORD116@Small nucleolar RNA, C/D box 116 cluster; small nucleolar RNA, C/D box 116-21
−2.10TCEA1Transcription elongation factor A (SII), 1
−2.10NCOR2Nuclear receptor corepressor 2
−2.10EFHC1EF-hand domain (C-terminal) containing 1
−2.10SLC11A2Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2
−2.11CDH11Cadherin 11, type 2, OB-cadherin (osteoblast)
−2.11NOSTRINNitric oxide synthase trafficker
−2.11EDEM1ER degradation enhancer, mannosidase α-like 1
−2.11ALDOCAldolase C, fructose-bisphosphate
−2.11NEDD1Neural precursor cell expressed, developmentally downregulated 1
−2.11SARSSeryl-tRNA synthetase
−2.11RN5S385RNA, 5S ribosomal 385
−2.11RAPGEF4Rap guanine nucleotide exchange factor (GEF) 4
−2.11ENOSF1Enolase superfamily member 1
−2.12PRKACBProtein kinase, cAMP-dependent, catalytic, β
−2.12CSNK1ECasein kinase 1, ε
−2.12ALG13Asparagine-linked glycosylation 13 homolog (S. cerevisiae)
−2.12DEPDC1DEP domain containing 1
−2.12IGFBP3Insulin-like growth factor binding protein 3
−2.12UACAUveal autoantigen with coiled-coil domains and ankyrin repeats
−2.12COL3A1Collagen, type III, α 1
−2.12IVNS1ABPInfluenza virus NS1A binding protein
−2.13EPB41L3Erythrocyte membrane protein band 4.1-like 3
−2.13STEAP1BSTEAP family member 1B
−2.13SOCS3Suppressor of cytokine signaling 3
−2.13MIR186microRNA 186
−2.13GFPT1 Glutamine-fructose-6-phosphate transaminase 1
−2.14MORC4MORC family CW-type zinc finger 4
−2.14ANKRD28Ankyrin repeat domain 28
−2.14MTMR11 Myotubularin-related protein 11
−2.14HLA-FMajor histocompatibility complex, class I, F
−2.14PIGK Phosphatidylinositol glycan anchor biosynthesis, class K
−2.14NUCB1Nucleobindin 1
−2.14ERAP1Endoplasmic reticulum aminopeptidase 1
−2.14PAN2PAN2 poly(A) specific ribonuclease subunit homolog (S. cerevisiae)
−2.14SYCP2LSynaptonemal complex protein 2-like
−2.15ADAMTS1ADAM metallopeptidase with thrombospondin type 1 motif, 1
−2.15IL1AInterleukin 1, α
−2.15ARHGAP29Rho GTPase-activating protein 29
−2.15C18orf54Chromosome 18 open reading frame 54
−2.15ENC1Ectodermal-neural cortex 1 (with BTB-like domain)
−2.15HSPG2Heparan sulfate proteoglycan 2
−2.16MIR492microRNA 492; keratin 19 pseudogene 2
−2.16DNASE2Deoxyribonuclease II, lysosomal
−2.16ABCA1ATP-binding cassette, sub-family A (ABC1), member 1
−2.16MAML3Mastermind-like 3 (Drosophila)
−2.16SNORA27Small nucleolar RNA, H/ACA box 27; 102; ribosomal protein L21
−2.16GSTT1Glutathione S-transferase θ 1
−2.17DCLK2Doublecortin-like kinase 2
−2.17PPP2R3CProtein phosphatase 2, regulatory subunit B', γ
−2.17MARCH1Membrane-associated ring finger (C3HC4) 1, E3 ubiquitin protein ligase
−2.17SPG11Spastic paraplegia 11 (autosomal recessive)
−2.17ANK3Ankyrin 3, node of Ranvier (ankyrin G)
−2.17LINGO2Leucine rich repeat and Ig domain containing 2
−2.17TNFRSF10BTumor necrosis factor receptor superfamily, member 10b
−2.17SRPX2Sushi-repeat containing protein, X-linked 2
−2.17ZNF41Zinc finger protein 41
−2.17MAN2C1Mannosidase, α, class 2C, member 1
−2.18PDE7BPhosphodiesterase 7B
−2.18EPAS1Endothelial PAS domain protein 1; uncharacterized LOC100652809
−2.18FN1Fibronectin 1
−2.18ETV4Ets variant 4
−2.18CTSOCathepsin O
−2.18MGAT4CMannosyl (α-1,3-)-glycoprotein β-1,4-N-acetylglucosaminyltransferase, isozyme C (putative)
−2.18R3HDM2R3H domain containing 2
−2.18AMDHD1Amidohydrolase domain containing 1
−2.18SNORA68Small nucleolar RNA, H/ACA box 68
−2.18SLC7A1Solute carrier family 7 (cationic amino acid transporter, y+ system), member 1
−2.19NID2Nidogen 2 (osteonidogen)
−2.19LXNLatexin
−2.19CTIFCBP80/20-dependent translation initiation factor
−2.19TRNAG36Transfer RNA glycine 36 (anticodon CCC); transfer RNA valine 34 (anticodon CAC) pseudogene
−2.19ST6GAL1ST6 β-galactosamide α-2,6-sialyltranferase 1
−2.19SCARNA23Small Cajal body-specific RNA 23
−2.19DPYDDihydropyrimidine dehydrogenase
−2.19DDR2Discoidin domain receptor tyrosine kinase 2
−2.18FN1Fibronectin 1
−2.18ETV4Ets variant 4
−2.18CTSOCathepsin O
−2.18MGAT4CMannosyl (α-1,3-)-glycoprotein β-1,4-N-acetylglucosaminyltransferase, isozyme C (putative)
−2.18R3HDM2R3H domain containing 2
−2.18AMDHD1Amidohydrolase domain containing 1
−2.18SNORA68Small nucleolar RNA, H/ACA box 68
−2.18SLC7A1Solute carrier family 7 (cationic amino acid transporter, y+ system), member 1
−2.19NID2Nidogen 2 (osteonidogen)
−2.19LXNLatexin
−2.19CTIFCBP80/20-dependent translation initiation factor
−2.19TRNAG36Transfer RNA glycine 36 (anticodon CCC); transfer RNA valine 34 (anticodon CAC) pseudogene
−2.19ST6GAL1ST6 β-galactosamide α-2,6-sialyltranferase 1
−2.19SCARNA23Small Cajal body-specific RNA 23
−2.19DPYDDihydropyrimidine dehydrogenase
−2.19DDR2Discoidin domain receptor tyrosine kinase 2
−2.19LGI1Leucine-rich, glioma inactivated 1
−2.19HLA-FMajor histocompatibility complex, class I, F
−2.20PSPHPhosphoserine phosphatase
−2.20HBG1Hemoglobin, γA; hemoglobin, γG; uncharacterized LOC100653319; uncharacterized LOC100653006
−2.20TMEM231Transmembrane protein 231
−2.20EML2Echinoderm microtubule-associated protein like-2
−2.21IGF2RInsulin-like growth factor 2 receptor
−2.21PYGBPhosphorylase, glycogen; brain
−2.21WSB1WD repeat and SOCS box containing 1
−2.22ITGBL1Integrin, β-like 1 (with EGF-like repeat domains)
−2.22PCBP3Poly(rC) binding protein 3
−2.22SERPINE2Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2
−2.22TAPBPTAP binding protein (tapasin)
−2.22ERGIC1Endoplasmic reticulum-golgi intermediate compartment (ERGIC) 1
−2.23PDLIM5PDZ and LIM domain 5
−2.23BCAT1Branched chain amino-acid transaminase 1, cytosolic
−2.23RN5S198RNA, 5S ribosomal 198
−2.23PCPyruvate carboxylase
−2.24BMPERBMP binding endothelial regulator
−2.24BACE2β-site APP-cleaving enzyme 2
−2.24CTNNAL1Catenin (cadherin-associated protein), α-like 1
−2.24ANKRD20A11PAnkyrin repeat domain 20 family, member A11, pseudogene; ankyrin repeat domain 20 family, member A8, pseudogene
−2.24SNORD116-29Small nucleolar RNA, C/D box 116-29
−2.24IFRD1Interferon-related developmental regulator 1
−2.25EDNRBEndothelin receptor type B
−2.25VN1R4Vomeronasal 1 receptor 4
−2.26NR4A2Nuclear receptor subfamily 4, group A, member 2
−2.26DKK1Dickkopf 1 homolog (Xenopus laevis)
−2.26OLFML2AOlfactomedin-like 2A
−2.26C6orf48Chromosome 6 open reading frame 48
−2.27SPRY3Sprouty homolog 3 (Drosophila)
−2.27PSAT1Phosphoserine aminotransferase 1
−2.27HOXA2Homeobox A2
−2.28DUSP1Dual specificity phosphatase 1
−2.28SLC44A1Solute carrier family 44, member 1
−2.28ITPRIPInositol 1,4,5-trisphosphate receptor interacting protein
−2.28OSMROncostatin M receptor
−2.28SUMF2Sulfatase modifying factor 2
−2.28S100A16S100 calcium binding protein A16
−2.28ITGB5Integrin, β5
−2.28SLC33A1Solute carrier family 33 (acetyl-CoA transporter), member 1
−2.28FOSL2FOS-like antigen 2
−2.28RBMS2RNA binding motif, single-stranded interacting protein 2
−2.28SOCS2Suppressor of cytokine signaling 2
−2.29EIF4EBP1Eukaryotic translation initiation factor 4E binding protein 1
−2.29RN5S449RNA, 5S ribosomal 449
−2.29IDH1Isocitrate dehydrogenase 1 (NADP+), soluble
−2.29UPP1Uridine phosphorylase 1
−2.29DPYSL2 Dihydropyrimidinase-like 2
−2.30CAMK2D Calcium/calmodulin-dependent protein kinase II δ
−2.30SHMT2Serine hydroxymethyltransferase 2 (mitochondrial)
−2.30MUC1Mucin 1, cell surface associated
−2.30ADAM9ADAM metallopeptidase domain 9
−2.31LOC100653286Aldo-keto reductase family 1 member C2-like; aldo-keto reductase family 1, member C2 (dihydrodiol dehydrogenase 2; bile acid binding protein; 3-α hydroxysteroid dehydrogenase, type III)
−2.31CD226CD226 molecule
−2.31ZNF449Zinc finger protein 449
−2.31PHLDB2Pleckstrin homology-like domain, family B, member 2
−2.31PLGRKTPlasminogen receptor, C-terminal lysine transmembrane protein
−2.31SPAG4Sperm-associated antigen 4
−2.31GADD45AGrowth arrest and DNA-damage-inducible, α
−2.31CGREF1Cell growth regulator with EF-hand domain 1
−2.31DUSP22Dual specificity phosphatase 22; dual specificity protein phosphatase 22-like
−2.31PMAIP1 Phorbol-12-myristate-13-acetate-induced protein 1
−2.31LOC100506948Uncharacterized LOC100506948; small nucleolar RNA, C/D box 116-28; 115-26; 115-13; 115-7; 116-22
−2.31ECE1Endothelin converting enzyme 1
−2.32PAQR5Progestin and adipoQ receptor family member V
−2.32LMF1Lipase maturation factor 1
−2.32SNORD13P2Small nucleolar RNA, C/D box 13 pseudogene 2
−2.32PLEKHG2Pleckstrin homology domain containing, family G (with RhoGef domain) member 2
−2.32TMX3Thioredoxin-related transmembrane protein 3
−2.33ZNF558Zinc finger protein 558
−2.33SOX9SRY (sex determining region Y)-box 9
−2.34SIL1SIL1 homolog, endoplasmic reticulum chaperone (S. cerevisiae)
−2.34FSD2Fibronectin type III and SPRY domain containing 2;
−2.34SNORD116-16Small nucleolar RNA, C/D box 116-16
−2.34ANGPTL4Angiopoietin-like 4
−2.34PABPC1LPoly(A) binding protein, cytoplasmic 1-like
−2.34PLCB4Phospholipase C, β4
−2.35BEST1Bestrophin 1
−2.35RNU7-35PRNA, U7 small nuclear 35 pseudogene
−2.36CDH2Cadherin 2, type 1, N-cadherin (neuronal)
−2.36HYOU1Hypoxia upregulated 1
−2.36ITGA6Integrin, α6
−2.37THBS3Thrombospondin 3
−2.37TM4SF18Transmembrane 4 L six family member 18
−2.37MTHFD1L Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like
−2.37PIRPirin (iron-binding nuclear protein); PIR-FIGF readthrough
−2.38MOCOSMolybdenum cofactor sulfurase
−2.38RHBDD1Rhomboid domain containing 1
−2.38ARL4DADP-ribosylation factor-like 4D
−2.38F2RL1Coagulation factor II (thrombin) receptor-like 1
−2.39RAPGEF5Rap guanine nucleotide exchange factor (GEF) 5
−2.39PCMTD2 Protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 2; long intergenic non-protein coding RNA 266-1
−2.39SREBF1Sterol regulatory element binding transcription factor 1
−2.40CPS1Carbamoyl-phosphate synthase 1, mitochondrial
−2.40ZEB2Zinc finger E-box binding homeobox 2
−2.40NRP2Neuropilin 2
−2.40HLCSHolocarboxylase synthetase [biotin-(proprionyl-CoA-carboxylase (ATP-hydrolysing) ligase]
−2.40CRIM1Cysteine rich transmembrane BMP regulator 1 (chordin-like)
−2.41ZC3H6Zinc finger CCCH-type containing 6
−2.41ARRDC4Arrestin domain containing 4
−2.41PDIA5Protein disulfide isomerase family A, member 5
−2.41WDFY2WD repeat and FYVE domain containing 2
−2.41VEGFCVascular endothelial growth factor C
−2.42CA5BCarbonic anhydrase VB, mitochondrial
−2.42CLN8 Ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation)
−2.42CYP20A1Cytochrome P450, family 20, subfamily A, polypeptide 1
−2.43AKR1B10Aldo-keto reductase family 1, member B10 (aldose reductase)
−2.43GPR126G protein-coupled receptor 126
−2.43TSPAN4Tetraspanin 4
−2.43FGGFibrinogen γ chain
−2.44RORARAR-related orphan receptor A
−2.44UGGT2UDP-glucose glycoprotein glucosyltransferase 2
−2.44DUSP5Dual specificity phosphatase 5
−2.45P4HA3Prolyl 4-hydroxylase, α polypeptide III
−2.45MARSMethionyl-tRNA synthetase
−2.45IGF2BP3Insulin-like growth factor 2 mRNA binding protein 3
−2.45TTC13Tetratricopeptide repeat domain 13
−2.45C16orf58Chromosome 16 open reading frame 58
−2.46BMP5Bone morphogenetic protein 5
−2.46SREBF2Sterol regulatory element binding transcription factor 2
−2.46NEDD9Neural precursor cell expressed, developmentally downregulated 9
−2.48OCLNOccludin; occludin pseudogene
−2.48PAG1Phosphoprotein associated with glycosphingolipid microdomains 1
−2.48PPFIBP1PTPRF interacting protein, binding protein 1 (liprin β1)
−2.48BTG1B-cell translocation gene 1, antiproliferative
−2.48XYLT1Xylosyltransferase I
−2.48CEP72Centrosomal protein 72 kDa
−2.48HNRNPU-AS1HNRNPU antisense RNA 1 (non-protein coding)
−2.49CLK1CDC-like kinase 1
−2.49VPS13CVacuolar protein sorting 13 homolog C (S. cerevisiae)
−2.50LAMA1Laminin, α1
−2.50PLD1Phospholipase D1, phosphatidylcholine-specific
−2.50AGXT2L2Alanine-glyoxylate aminotransferase 2-like 2
−2.50SLCO5A1Solute carrier organic anion transporter family, member 5A1
−2.51CARSCysteinyl-tRNA synthetase
−2.51ACAD11Acyl-CoA dehydrogenase family, member 11; nephronophthisis 3 (adolescent); NPHP3-ACAD11 readthrough
−2.51SLC2A14Solute carrier family 2 (facilitated glucose transporter), member 14
−2.52SCCPDHSaccharopine dehydrogenase (putative)
−2.52NT5E5′-nucleotidase, ecto (CD73)
−2.53AADACArylacetamide deacetylase (esterase)
−2.53TMEM106BTransmembrane protein 106B
−2.54GDPD1 Glycerophosphodiester phosphodiesterase domain containing 1
−2.55DNERδ/notch-like EGF repeat containing
−2.55SLITRK4SLIT and NTRK-like family, member 4
−2.55ST3GAL1ST3 β-galactoside α-2,3-sialyltransferase 1
−2.55SLC8A1Solute carrier family 8 (sodium/calcium exchanger), member 1
−2.55SPDYE8PSpeedy homolog E8 (Xenopus laevis), pseudogene
−2.55SLC9B1Solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member 1; solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member 1 pseudogene 2; solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member 1 pseudogene 3
−2.56ZP3Zona pellucida glycoprotein 3 (sperm receptor)
−2.56BCAR3Breast cancer anti-estrogen resistance 3
−2.57GABBR2γ-aminobutyric acid (GABA) B receptor, 2
−2.57CD55CD55 molecule, decay accelerating factor for complement (Cromer blood group)
−2.57GALNT3 UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3)
−2.57THBS1Thrombospondin 1
−2.57MIR21microRNA 21
−2.58SESN2Sestrin 2
−2.59FLNBFilamin B, β
−2.59EFNA5Ephrin-A5
−2.59PTPRBProtein tyrosine phosphatase, receptor type, B
−2.59PIONPigeon homolog (Drosophila)
−2.60EFEMP1EGF containing fibulin-like extracellular matrix protein 1
−2.60DUSP4Dual specificity phosphatase 4
−2.61RTN1Reticulon 1
−2.61DGKDDiacylglycerol kinase, δ 130 kDa
−2.61ANTXR1Anthrax toxin receptor 1
−2.61SUCLG2Succinate-CoA ligase, GDP-forming, β subunit
−2.61LOC100506965Uncharacterized LOC100506965
−2.62LAMC1laminin, γ1 (formerly LAMB2)
−2.63CEP70Centrosomal protein 70 kDa
−2.64ABCA8ATP-binding cassette, sub-family A (ABC1), member 8
−2.65SERPINB9Serpin peptidase inhibitor, clade B (ovalbumin), member 9
−2.65PDE1CPhosphodiesterase 1C, calmodulin-dependent 70 kDa
−2.65ACSS3Acyl-CoA synthetase short-chain family member 3
−2.66SCG2Secretogranin II
−2.67SLC39A8Solute carrier family 39 (zinc transporter), member 8
−2.67F2RCoagulation factor II (thrombin) receptor
−2.67MMEMembrane metallo-endopeptidase
−2.68LCP1Lymphocyte cytosolic protein 1 (L-plastin)
−2.68CFHComplement factor H
−2.68NCAM2Neural cell adhesion molecule 2
−2.70HINT3Histidine triad nucleotide binding protein 3
−2.70GPR37G protein-coupled receptor 37 (endothelin receptor type B-like)
−2.71PPAP2BPhosphatidic acid phosphatase type 2B
−2.72LAMB1Laminin, β1
−2.73GALNTL1 UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-like 1
−2.73PDK1Pyruvate dehydrogenase kinase, isozyme 1
−2.74TRMT2BtRNA methyltransferase 2 homolog B (S. cerevisiae)
−2.74SSFA2Sperm-specific antigen 2
−2.75TMEM100Transmembrane protein 100
−2.75RAB39BRAB39B, member RAS oncogene family
−2.75SORBS2Sorbin and SH3 domain containing 2
−2.76RGS2Regulator of G-protein signaling 2, 24 kDa
−2.76SERPIND1Serpin peptidase inhibitor, clade D (heparin cofactor), member 1
−2.77LOC344887NmrA-like family domain containing 1 pseudogene
−2.77PRKAA2Protein kinase, AMP-activated, α2 catalytic subunit
−2.77PYCR1 Pyrroline-5-carboxylate reductase 1
−2.77MIR32microRNA 32
−2.77TTC32Tetratricopeptide repeat domain 32
−2.78CCDC68Coiled-coil domain containing 68
−2.78GPR22G protein-coupled receptor 22
−2.79ULBP1UL16 binding protein 1
−2.79AXLAXL receptor tyrosine kinase
−2.79ERVK-9Endogenous retrovirus group K, member 9; endogenous retrovirus group K, member 4; endogenous retrovirus group K, member 19
−2.79DOCK4Dedicator of cytokinesis 4
−2.80PTPRMProtein tyrosine phosphatase, receptor type, M
−2.80STC2Stanniocalcin 2
−2.80PHLDA1Pleckstrin homology-like domain, family A, member 1
−2.81FAM198BFamily with sequence similarity 198, member B
−2.81NR1D1Nuclear receptor subfamily 1, group D, member 1
−2.82NUP210Nucleoporin 210 kDa
−2.83PCID2PCI domain containing 2
−2.83ZBTB38Zinc finger and BTB domain containing 38
−2.83PIGF Phosphatidylinositol glycan anchor biosynthesis, class F
−2.83GLRXP3Glutaredoxin (thioltransferase) pseudogene 3
−2.74SSFA2Sperm specific antigen 2
−2.84HSPA13Heat shock protein 70 kDa family, member 13
−2.85RBMS3RNA binding motif, single stranded interacting protein 3
−2.88SMYD3SET and MYND domain containing 3
−2.88ASNSAsparagine synthetase (glutamine-hydrolyzing)
−2.89TFPI2Tissue factor pathway inhibitor 2
−2.89TNFRSF19Tumor necrosis factor receptor superfamily, member 19
−2.90CRY1Cryptochrome 1 (photolyase-like)
−2.90IL1RAPInterleukin 1 receptor accessory protein
−2.91AGAAspartyl glucose aminidase
−2.93FBXO32F-box protein 32
−2.94LIFLeukemia inhibitory factor
−2.94TMEM194BTransmembrane protein 194B
−2.95FAM115AFamily with sequence similarity 115, member A
−2.96PTPRDProtein tyrosine phosphatase, receptor type, D
−2.98HERPUD1 Homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1
−2.98ALPK2α-kinase 2
−3.00BMP6Bone morphogenetic protein 6
−3.00LONP1Lon peptidase 1, mitochondrial
−3.02CCPG1Cell cycle progression 1; DYX1C1-CCPG1 readthrough (non-protein coding)
−3.03CHAC1ChaC, cation transport regulator homolog 1 (E. coli)
−3.04XBP1X-box binding protein 1
−3.05FHAD1Forkhead-associated (FHA) phosphopeptide binding domain 1
−3.07GREM2Gremlin 2
−3.07CXCL2Chemokine (C-X-C motif) ligand 2
−3.07KLRC3Killer cell lectin-like receptor subfamily C, member 3; member 2
−3.08CD36CD36 molecule (thrombospondin receptor)
−3.08LINC00173Long intergenic non-protein coding RNA 173
−3.08MIRLET7F1microRNA let-7f-1
−3.09GDF15Growth differentiation factor 15
−3.09VEGFAVascular endothelial growth factor A
−3.11COL4A6Collagen, type IV, α6
−3.11ANTXR2Anthrax toxin receptor 2
−3.12EDIL3EGF-like repeats and discoidin I-like domains 3
−3.12SEPP1Selenoprotein P, plasma, 1
−3.12COL4A5Collagen, type IV, α5
−3.12RNF19ARing finger protein 19A, E3 ubiquitin protein ligase
−3.12SNRPA1Small nuclear ribonucleoprotein polypeptide A'
−3.12P4HA1Prolyl 4-hydroxylase, α polypeptide I
−3.13ANK2Ankyrin 2, neuronal
−3.13TUBE1Tubulin, ε1
−3.14GPR65G protein-coupled receptor 65
−3.15FRKFyn-related kinase
−3.15SLC2A13Solute carrier family 2 (facilitated glucose transporter), member 13
−3.15CTHCystathionase (cystathionine γ-lyase)
−3.15PLA2G7Phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
−3.16PCK2Phosphoenolpyruvate carboxykinase 2 (mitochondrial)
−3.17PRSS23Protease, serine, 23
−3.18FBXL13F-box and leucine-rich repeat protein 13
−3.18B4GALT1UDP-Gal:βGlcNAc β 1,4-galactosyltransferase, polypeptide 1
−3.19CXCL5Chemokine (C-X-C motif) ligand 5
−3.19PHGDHPhosphoglycerate dehydrogenase
−3.19SLC4A7Solute carrier family 4, sodium bicarbonate cotransporter, member 7
−3.19DDIT4 DNA-damage-inducible transcript 4
−3.21RSPO3R-spondin 3
−3.21OGTO-linked N-acetylglucosamine (GlcNAc) transferase
−3.22FAM129AFamily with sequence similarity 129, member A
−3.22CDH13Cadherin 13, H-cadherin (heart)
−3.23PLAUPlasminogen activator, urokinase
−3.24SEMA3CSema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C
−3.26CTBSChitobiase, di-N-acetyl-
−3.27SLC4A11Solute carrier family 4, sodium borate transporter, member 11
−3.28CSGALNACT1Chondroitin sulfate N-acetylgalactosaminyltransferase 1
−3.29PDE1APhosphodiesterase 1A, calmodulin-dependent
−3.29BDNFBrain-derived neurotrophic factor
−3.29SAMD13Sterile α motif domain containing 13
−3.30KLRC4-KLRK1KLRC4-KLRK1 readthrough; killer cell lectin-like receptor subfamily K, member 1
−3.31NRN1Neuritin 1
−3.31SEL1L3Sel-1 suppressor of lin-12-like 3 (C. elegans)
−3.33PDE3APhosphodiesterase 3A, cGMP-inhibited
−3.33FBN2Fibrillin 2
−3.33NCAM1Neural cell adhesion molecule 1
−3.34RAB31RAB31, member RAS oncogene family
−3.35DEFB1Defensin, β1
−3.36PLAURPlasminogen activator, urokinase receptor
−3.36TSC22D3TSC22 domain family, member 3
−3.36CNTN1Contactin 1
−3.37PCSK1Proprotein convertase subtilisin/kexin type 1
−3.38ADAMTS6ADAM metallopeptidase with thrombospondin type 1 motif, 6
−3.40LOXL2Lysyl oxidase-like 2
−3.40LURAP1LLeucine rich adaptor protein 1-like
−3.41SCDStearoyl-CoA desaturase (δ-9-desaturase)
−3.42PSD3Pleckstrin and Sec7 domain containing 3
−3.43EPSTI1Epithelial stromal interaction 1 (breast)
−3.44PLA2R1Phospholipase A2 receptor 1, 180 kDa
−3.45CDR1Cerebellar degeneration-related protein 1, 34 kDa
−3.46CYR61Cysteine-rich, angiogenic inducer, 61
−3.46KLRC2Killer cell lectin-like receptor subfamily C, member 2
−3.46BHLHE40Basic helix-loop-helix family, member e40
−3.47FSTL1Follistatin-like 1
−3.52SLC7A2Solute carrier family 7 (cationic amino acid transporter, y+ system), member 2
−3.53GTPBP2GTP binding protein 2
−3.53THSD4Thrombospondin, type I, domain containing 4
−3.54CPED1Cadherin-like and PC-esterase domain containing 1
−3.54ESM1Endothelial cell-specific molecule 1
−3.54SEMA3ASema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A
−3.55ASS1P11Argininosuccinate synthetase 1 pseudogene 11
−3.56ITGA3Integrin, α3 (antigen CD49C, α3 subunit of VLA-3 receptor)
−3.57SAT1Spermidine/spermine N1-acetyltransferase 1
−3.57PYROXD1Pyridine nucleotide-disulphide oxidoreductase domain 1
−3.59WDR69WD repeat domain 69
−3.59SLC6A9Solute carrier family 6 (neurotransmitter transporter, glycine), member 9
−3.62PAPPA2Pappalysin 2
−3.63MALAT1 Metastasis-associated lung adenocarcinoma transcript 1 (non-protein coding)
−3.64LAMA5Laminin, α5
−3.65EDN1Endothelin 1
−3.71SMOXSpermine oxidase
−3.72MIR29AmicroRNA 29a
−3.74TFPITissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor)
−3.75GLRXGlutaredoxin (thioltransferase)
−3.79GPRIN3GPRIN family member 3
−3.79TRPC6Transient receptor potential cation channel, subfamily C, member 6
−3.81IL8Interleukin 8
−3.86IL18R1Interleukin 18 receptor 1
−3.89LAMB3Laminin, β3
−3.90PDCD1LG2Programmed cell death 1 ligand 2
−3.93STARD4StAR-related lipid transfer (START) domain containing 4
−3.93DLG2Discs, large homolog 2 (Drosophila)
−3.96LSAMPLimbic system-associated membrane protein
−4.00PITPNC1 Phosphatidylinositol transfer protein, cytoplasmic 1
−4.03APLNApelin
−4.03CTGFConnective tissue growth factor
−4.06LRRC63Leucine rich repeat containing 63
−4.08PLATPlasminogen activator, tissue
−4.15SLC25A37Solute carrier family 25 (mitochondrial iron transporter), member 37
−4.19NUPR1Nuclear protein, transcriptional regulator, 1
−4.23TSPAN8Tetraspanin 8
−4.24SPOCK1Sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 1
−4.25NRCAMNeuronal cell adhesion molecule
−4.25C3orf49Chromosome 3 open reading frame 49
−4.35TMEM144Transmembrane protein 144
−4.41PARK2Parkinson protein 2, E3 ubiquitin protein ligase (parkin)
−4.44SCARA5Scavenger receptor class A, member 5 (putative)
−4.53ABCC3ATP-binding cassette, sub-family C (CFTR/MRP), member 3
−4.60THSD7AThrombospondin, type I, domain containing 7A
−4.66IL6Interleukin 6 (interferon, β2)
−4.67CDH19Cadherin 19, type 2
−4.70VLDLRVery low density lipoprotein receptor
−4.78STC1Stanniocalcin 1
−4.81ABI3BPABI family, member 3 (NESH) binding protein
−4.90TNFAIP3Tumor necrosis factor, α-induced protein 3
−4.90DUSP6Dual specificity phosphatase 6
−4.90SEMA3DSema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3D
−4.93CBS Cystathionine-β-synthase
−4.95DPP10 Dipeptidyl-peptidase 10 (non-functional)
−5.19SLC16A4Solute carrier family 16, member 4 (monocarboxylic acid transporter 5)
−5.22CLDN1Claudin 1
−5.28KIAA0825KIAA0825
−5.35PLAC4Placenta-specific 4
−5.38EPHA4EPH receptor A4
−5.48ALDH1L2Aldehyde dehydrogenase 1 family, member L2
−5.51DDIT3 DNA-damage-inducible transcript 3
−5.51TXNIPThioredoxin interacting protein
−5.52WARSTryptophanyl-tRNA synthetase
−5.69PRICKLE1Prickle homolog 1 (Drosophila)
−5.81CLGNCalmegin
−5.81ERRFI1ERBB receptor feedback inhibitor 1
−5.94SMOC1SPARC related modular calcium binding 1
−6.03ABCC9ATP-binding cassette, sub-family C (CFTR/MRP), member 9
−6.05ASS1Argininosuccinate synthase 1
−6.20KCNE4Potassium voltage-gated channel, Isk-related family, member 4
−6.23C12orf39Chromosome 12 open reading frame 39
−6.24LCN1Lipocalin 1
−6.28PAPPA Pregnancy-associated plasma protein A, pappalysin 1
−6.44TMEM27Transmembrane protein 27
−6.70CHL1Cell adhesion molecule with homology to L1CAM (close homolog of L1)
−6.83SUCNR1Succinate receptor 1
−7.16AREGAmphiregulin
−7.57HPGDSHematopoietic prostaglandin D synthase
−7.62ANXA3Annexin A3
−8.16SLC2A3Solute carrier family 2 (facilitated glucose transporter), member 3
−8.34TGFB2Transforming growth factor, β2
−8.40GABREγ-aminobutyric acid (GABA) A receptor, ε; microRNA 452; microRNA 224
−8.88RNY1P5RNA, Ro-associated Y1 pseudogene 5
−9.52RPE65Retinal pigment epithelium-specific protein 65 kDa
−9.54CD274CD274 molecule
−12.33FSTFollistatin
−12.69GPR133G protein-coupled receptor 133
−13.11SERPINB11Serpin peptidase inhibitor, clade B (ovalbumin), member 11 (gene/pseudogene)
−15.73IL1RL1Interleukin 1 receptor-like 1

Table II shows that 59 genes were downregulated with >4-fold change including the DDIT3 gene, associated with DNA damage, while 97 genes had a >3- to 4-fold change, including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with the cell cycle and 321 genes exhibited a >2- to 3-fold change including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with the cell cycle; the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B genes, associated with cell survival; and the ARHAP29 and CADM2 genes, associated with cell migration and invasion.

Curcumin affects the gene expression scores as measured by GeneGo analysis program in NCI-H460 cells by the number of pathway networks

Curcumin-treated or -untreated cells were performed by cDNA microarray and then processed using GeneGo analysis. The results are shown in Figs. 1Figure 23 for top, second and third scores, respectively. The analysis results were mapped on the processes as presented in possible signal effects. Red indicated upregulated genes and blue, the downregulated genes. Circles indicated different intensities indicating different enhancing or inhibitions in curcumin-treated NCI-H460 cells.

Discussion

It has been demonstrated that curcumin induced biological activities including anticancer function in vitro and in vivo. However, how curcumin affects gene expression and the associated signaling pathways in human lung cancer cells remains to be determined. Thus, we investigated the up- and downregulation of associated genes with cell cycle, DNA damage, cell survival and cell migration and invasion in NCI H460 cells. In the present study, we found several genes involved DNA damage and repair were increased, such as cyclin E2 (CCNE2), which was increased 3.79-fold. It has also been reported that following cell induction DNA damage led to cell cycle arrest (21). The tumor protein p53 inducible nuclear protein 1 (TP53INP1) was increased 2.09-fold and after DNA damage the p53 protein expression was also increased (22).

The results showed that the TP53INP1 gene, associated with DNA damage was increased 2.09-fold, the CDC6, TAKMIP2, CDCA5, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle were increased 2.56-, 2.31-, 2.26-, 2.12-, 2.11-, 2.09-, 2.06-, 2.02- and 2.02-fold, respectively, associated with cell cycle, while the CARD6, ID1 and ID2 genes, associated with cell survival were increased 2.99-, 2.70- and 2.12-fold. It was also found that the BRMS1L gene, associated with cell migration and invasion, was increased 2.27-fold. It was reported that tumor protein 53-induced nuclear protein 1 (TP53INP1) is a stress-induced p53-target gene function that represses tumorigenesis (23). The cell cycle-dependent centrosomal localization of Cdc6 in the S and G2 phases is considered to have a novel function of Cdc6 in centrosomes (24). CDCA5 and CDK5 have been found to play an important role in the cell cycle (25). It was reported that the mitotic CDK14/cyclin Y complex promotes Wnt signaling (26). Moreover, Cdc25 is known to be involved cell cycle regulation (27). Caspase recruitment domain 6 (CARD6), a microtubule-interacting protein, belongs to the CARD family (28). CARD6 may be a novel target for the treatment of pathological cardiac hypertrophy and failure (29). ID (inhibitor of differentiation and DNA binding) comprises the ID1, ID2, ID3 and ID4 proteins, which are involved in cancer progression (30). ID1 (inhibitor of differentiation and DNA binding 1) was reported to strongly correlate with various types of tumors, including lung cancer (31,32).

The results also show that curcumin decreased several gene expressions associated with DNA damage, cell cycle, cell survival and cell migration and invasion. For example, DDIT3, DDIT4, GADD45A and CGREF1 were decreased 5.51-, 3.19-, 2.31- and 2.31-fold, respectively, which was associated with DNA damage. Curcumin decreased 3.02-fold of the CCPG1 gene expression which was associated with cell cycle progression and the TNFRSF10B, TSSC1, GAS5 and TNFRSF11B genes were decreased 2.17-, 2.03-, 2.03- and 2.02-fold, which was associated with cell survival. Furthermore, curcumin decreased two gene expressions at 2.15- and 2.06-fold, respectively, which associated with cell migration. It was reported that the induction of DNA-damage-inducible transcript 3 (DDIT3) was observed in the liver of mice exposed to coal mining and this gene is frequently upregulated in response to cell stress and DNA damage (33). DNA-damage-inducible transcript 4 (DDIT4) is involved in multiple biological settings such as inhibiting mTORC1 signaling and regulating the production of reactive oxygen species (35,36), which was also associated with DNA damage. It was demonstrated that myristicin, an allylbenzene, is a major active component of various spices inducing DNA damage signalling (ATM) and stress response (GADD45A and GADD45G) in leukemia cells (34). The TNFRSF10B gene which encodes the apop-totic death receptor TNFRSF10B was associated with cell death (38). It was also reported that the recurrent amplification of MYC and TNFRSF11B in 8q24 is associated with poor survival in patients with gastric cancer survival (35). Growth arrest-specific 5 (GAS5) is a non-coding gene that hosts a number of small nucleolar RNAs (snoRNAs) and it has been suggested to play a tumor suppressive role (36,37).

The results of the present study indicated that a number of genes were associated with DNA damage and repair, cell cycle check point, cell survival and cell migration and invasion in NCI-H460 cells following exposure to curcumin. Based on these observations, we determined these associated genes with possible signaling complex interactions. Thus, future investigations are needed to expand or append our current findings and possible understandings. These genes were affected by curcumin, which provides more information for the understanding of the cytotoxic mechanism of curcumin at the genetic level. Furthermore, it provides potentially useful biomarkers or targets in clinic for the diagnosis and treatment of human lung cancer.

Acknowledgments

This study was supported by grant RD2015–032 from the National Yang-Ming University Hospital, Yilan, Taiwan.

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October-2015
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Chiang I, Wang W, Liu H, Yang S, Tang N and Chung J: Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro. Oncol Rep 34: 1853-1874, 2015
APA
Chiang, I., Wang, W., Liu, H., Yang, S., Tang, N., & Chung, J. (2015). Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro. Oncology Reports, 34, 1853-1874. https://doi.org/10.3892/or.2015.4159
MLA
Chiang, I., Wang, W., Liu, H., Yang, S., Tang, N., Chung, J."Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro". Oncology Reports 34.4 (2015): 1853-1874.
Chicago
Chiang, I., Wang, W., Liu, H., Yang, S., Tang, N., Chung, J."Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro". Oncology Reports 34, no. 4 (2015): 1853-1874. https://doi.org/10.3892/or.2015.4159