TI - Network analysis NASP overexpression . AB - Network analysis assembled three networks from up-regulated genes after NASP overexpression ( table 4A ) . The network with the highest score ( table 4A , network #1 ) included gene products associated with TNF , which is a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor ( TNF ) superfamily . This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation and differentiation , and has been implicated in cancer and autoimmune diseases [25] . In response to TNF and growth factors , STAT1 protein ( found up-regulated in NASP overexpressing cells ) , is PHOSphorylated and translocates to the nucleus where it acts as a transcription activator [26] , mediating the expression of a variety of genes . In this network ATF3 ( activating transcription factor ) is connected with TNF , which is known to increase the expression of human ATF3 mRNA in LoVo cells [27] . A . UPREGULATED GENES Focus genes Interacting genes Score Top functions 1 ATF3 , CXCL2 , DUSP5 , GDF15 , IFI6 , IFI27 , IFIH1 , IFITM1 , IRF7 , IRF9 , KRT34 , OAS1 , OAS3 ( includes EG : 4940 ) , OASL , PARP9 , RELB , STAT1 , TNF , TNFAIP3 Cyclooxygenase , IFN Beta , Ifn gamma , IL1/IL6/TNF , Interferon alpha , Interferon beta , IRF , ISGF3 , LDL , MHC Class I , NF-kappaB , NfkB-RelA , SAA@ , Sod , Stat1-Stat2 , Tlr 44 organismal injury and abnormalities , gene expression , immune response 2 CXCL1 , CXCL3 , DDIT3 , DKK1 , EREG , OSL1 , IL8 , L11 , IL1A , PHLDA1 , PTGS2 , PPP1R15A ( includes EG : 23645 ) Akt , ALP , Ap1 , Cbp/p300 , Creb , ERK , hCG , Hsp27 , Hsp90 , IKK , IL1 , JAK , MAP2K1/2 , Nos , P38 MAPK , Pdgf , PDGF BB , PI3K , Pkcs , PLC , STAT , Tgf beta , Vegf 25 cellular growth and proliferation , cellular movement , hematological system function 3 BIRC3 , ETV5 , GADD45A , IL6 , RRAD , STC2 ABLIM , ADCY , CAP2 , Ck2 , Caspase , Cytochrome C , FSH , DYRK3 , Histone h3 , Hsp70 , IL12 , IL1/IL6/TNF , IL1F8 , IL1F9 , Insulin , Jnk , Mapk , Nfat , NFkB , Pka , Proteasome , Rac , Ras , RNA polymerase II , STAT5a/b , UBR2 , Vacuolar H+ ATPase , ZNF274 , ZNF675 10 infectious disease , cell cycle , cancer B . DOWNREGULATED GENES Focus genes Interacting genes Score Top functions 1 AQP5 , EGR1 , FOS , KRT19 , LMO1 , NFE2 , TNF ADCYAP1 , AKR1B10 , ARF4 , ASC2 , BARX2 , BPI , CCL9 , COBRA1 , CXCL16 , DGCR6 , EMB , FOXF1 , GFPT2 , HMBS , IL1/IL6/TNF , IL1F9 , JUN , LOC729687 , LTBP2 , MFHAS1 , NFkB , RFTN1 , SFI1 , SLC7A1 , TNIP3 , TRAFD1 , Vacuolar H+ ATPase , WNT10A 17 gene expression , cell cycle , cellular developmentThe other two networks ( table 4A , network #2 and #3 ) contained groups of interacting proteins that included GADD45A , interleukins IL6 , IL1A , chemokines CXCL3 , CXCL1 and NF-kappaB . NF-kappaB is a transcription factor that mediates the transcription of proteins involved in cell survival , proliferation , and inflammatory responses , and is the subject of active research for anti-cancer therapy [28] . The protein encoded by the GADD45A gene induces apoptosis and cell cycle arrest by maintaining p38 and c-JNK MAPK activation in keratinocytes . The absence of Gadd45a results in loss of sustained p38/JNK MAPK activity that leads to inadequate p53 activation and loss of normal activation of G1 and G2 checkpoints [29] . Only one network was assembled from the down-regulated genes after NASP overexpression ( table 4B ) . It included TNF , FOS , LMO1 , EGR1 , NFE2 , KRT19 and AQP5 . TNF , FOS and NFkappaB are the "hubs" that suggests possible involvement of this network in cell proliferation , differentiation and transformation . The presence of transcriptional regulator EGR suggests cancer suppressor activity [30] .