Role of early growth response 1 in liver metabolism and liver cancer

Abstract

The liver is an essential organ for nutrient and drug metabolism - possessing the remarkable ability to sense environmental and metabolic stimuli and provide an optimally adaptive response. Early growth response 1 (Egr1), an immediate early transcriptional factor which acts as a coordinator of the complex response to stress, is induced during liver injury and controls the expression of a wide range of genes involved in metabolism, cell proliferation, and inflammation. In support of an important role of Egr1 in liver injury and repair, deficiency of Egr1 delays liver regeneration process. The known upstream regulators of Egr1 include, but are not limited to, growth factors (e.g. transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, hepatocyte growth factor), nuclear receptors (e.g. hepatocyte nuclear factor 4α, small heterodimer partner, peroxisome proliferator-activated receptor-γ), and other transcription factors (e.g. Sp1, E2F transcription factor 1). Research efforts using various animal models such as fatty liver, liver injury, and liver fibrosis contribute greatly to the elucidation of Egr1 function in the liver. Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide due to the heterogeneity and the late stage at which cancer is generally diagnosed. Recent studies highlight the involvement of Egr1 in HCC development. The purpose of this review is to summarize current studies pertaining to the role of Egr1 in liver metabolism and liver diseases including liver cancer.

Keywords

Early growth response 1 / liver / fibrosis / injury / liver cancer

References

[1] Milbrandt J.A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor..Science1987;238:797-9

[2] Kaufmann K,Thiel G.The extracellular signal-regulated protein kinases Erk1/Erk2 stimulate expression and biological activity of the transcriptional regulator Egr-1..Biol Chem2001;382:1077-81

[3] Gashler AL,Sukhatme VP.A novel repression module, an extensive activation domain, and a bipartite nuclear localization signal defined in the immediate-early transcription factor Egr-1..Mol Cell Biol1993;13:4556-71 PMCID:PMC360074

[4] Cui L,Zhu L,Alshatwi A.Zinc depletion reduced Egr-1 and HNF-3beta expression and apolipoprotein A-I promoter activity in Hep G2 cells..Am J Physiol Cell Physiol2002;283:C623-30

[5] Duclot F.The role of early growth response 1 (EGR1) in brain plasticity and neuropsychiatric disorders..Front Behav Neurosci2017;11:35 PMCID:PMC5337695

[6] Swirnoff AH,Svaren J,Zimonjic DB,Milbrandt J.Nab1, a corepressor of NGFI-A (Egr-1), contains an active transcriptional repression domain..Mol Cell Biol1998;18:512-24 PMCID:PMC115883

[7] Sevetson BR,Milbrandt J.A novel activation function for NAB proteins in EGR-dependent transcription of the luteinizing hormone beta gene..J Biol Chem2000;275:9749-57

[8] Li XJ,Xu Y,Xia AD,Qian GX.Ionizing radiation-regulated killing of human hepatoma cells by liposome-mediated CDglyTK gene delivery..Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai).2003;35:64-70(in Chinese)

[9] Keeton AB,Bennett WL,Venable DY.Insulin-regulated expression of Egr-1 and Krox20: dependence on ERK1/2 and interaction with p38 and PI3-kinase pathways..Endocrinology2003;144:5402-10

[10] Chen SJ,Ishida W,Takagawa S,Varga J.The early-immediate gene EGR-1 is induced by transforming growth factor-beta and mediates stimulation of collagen gene expression..J Biol Chem2006;281:21183-97

[11] Zhang Y,Gonzalez FJ.Diurnal regulation of the early growth response 1 (Egr-1) protein expression by hepatocyte nuclear factor 4alpha (HNF4alpha) and small heterodimer partner (SHP) cross-talk in liver fibrosis..J Biol Chem2011;286:29635-43 PMCID:PMC3191004

[12] Zhang Y,Xu J,Copple B,Wang L.E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network..Hepatology2014;60:919-30 PMCID:PMC4146672

[13] Zhu HY,Wang HT,Tao K,Liu JQ,Li J,He T,Hu DH.Peroxisome proliferator-activated receptor-gamma agonist inhibits collagen synthesis in human keloid fibroblasts by suppression of early growth response-1 expression through upregulation of miR-543 expression..Am J Cancer Res2016;6:1358-70 PMCID:PMC4937738

[14] Dussmann P,Vogel S,Zimmermann R,Schaper W,Deindl E.Live in vivo imaging of Egr-1 promoter activity during neonatal development, liver regeneration and wound healing..BMC Dev Biol2011;11:28 PMCID:PMC3120781

[15] Christy B.DNA binding site of the growth factor-inducible protein Zif268..Proc Natl Acad Sci U S A1989;86:8737-41 PMCID:PMC298363

[16] Fagerberg L,Oksvold P,Djureinovic D,Habuka M,Danielsson A,Asplund A,Lundberg E,Skogs M,Berling H,Mulder J,Schwenk JM,Danielsson F,Sivertsson A,Forsberg M,Olsson I,Huss M,Ponten F.Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics..Mol Cell Proteomics2014;13:397-406 PMCID:PMC3916642

[17] Yang H,Noh JK,Park CJ,Kim KK.Expression pattern of early growth response gene 1 during olive flounder (paralichthys olivaceus) embryonic development..Dev Reprod2014;18:233-40 PMCID:PMC4415633

[18] Pritchard MT,Nagy LE.Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice..Am J Physiol Gastrointest Liver Physiol2011;300:G1124-31 PMCID:PMC3119116

[19] Veyrac A,Bruel-Jungerman E,Kleine Borgmann FB,Laroche S.Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning..Proc Natl Acad Sci U S A2013;110:7062-7 PMCID:PMC3637756

[20] Zhang J,Sun T,Huang S,Abate N,Xin HB,Fu M.Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2..Sci Rep2013;3:1476 PMCID:PMC3600596

[21] Yang YM,Li X,Wang ZC.TRAIL overexpression co-regulated by Egr1 and HRE enhances radiosensitivity of hypoxic A549 cells depending on its apoptosis inducing role..Oncol Rep2017;37:533-9

[22] Bhattacharyya S,Fang F,Feghali-Bostwick C.Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy..Matrix Biol2011;30:235-42 PMCID:PMC3135176

[23] Kobayashi D,Kamagata C,Tsuji N,Yagihashi A.Overexpression of early growth response-1 as a metastasis-regulatory factor in gastric cancer..Anticancer Res2002;22:3963-70

[24] Gokey NG,Gillian-Daniel AL.Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression..J Biol Chem2011;286:29501-10 PMCID:PMC3190990

[25] Mohn KL,Melby AE.Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families..J Biol Chem1990;265:21914-21

[26] Rui L.Energy metabolism in the liver..Compr Physiol2014;4:177-97 PMCID:PMC4050641

[27] Bechmann LP,Gerken G,Trauner M.The interaction of hepatic lipid and glucose metabolism in liver diseases..J Hepatol2012;56:952-64

[28] Josefsen K,Buschard K.Glucose induces early growth response gene (Egr-1) expression in pancreatic beta cells..Diabetologia1999;42:195-203

[29] Hasan RN,Harada S.Differential regulation of early growth response gene-1 expression by insulin and glucose in vascular endothelial cells..Arterioscler Thromb Vasc Biol2003;23:988-93

[30] Harada S,Holgado-Madruga M.Grb-2-associated binder-1 is involved in insulin-induced egr-1 gene expression through its phosphatidylinositol 3'-kinase binding site..DNA Cell Biol2001;20:223-9

[31] Gousseva N,Chesterman CN.Early growth response factor-1 mediates insulin-inducible vascular endothelial cell proliferation and regrowth after injury..J Cell Biochem2001;81:523-34

[32] Barroso I.Insulin-induced early growth response gene (Egr-1) mediates a short term repression of rat malic enzyme gene transcription..J Biol Chem1999;274:17997-8004

[33] Streeper RS,Ayala JE,Goldman JK,O'Brien RM.A phorbol ester-insensitive AP-1 motif mediates the stimulatory effect of insulin on rat malic enzyme gene transcription..Mol Endocrinol1998;12:1778-91

[34] Kilbourne EJ,Harnish DC,Karathanasis SK.Involvement of early growth response factor Egr-1 in apolipoprotein AI gene transcription..J Biol Chem1995;270:7004-10

[35] Shen N,Pan FY,Xue B.An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism..J Biol Chem2011;286:14508-15 PMCID:PMC3077649

[36] Biddinger SB.From mice to men: insights into the insulin resistance syndromes..Annu Rev Physiol2006;68:123-58

[37] Fujishiro M,Katagiri H,Ogihara T,Onishi Y,Abe M,Fukushima Y,Oka Y.Three mitogen-activated protein kinases inhibit insulin signaling by different mechanisms in 3T3-L1 adipocytes..Mol Endocrinol2003;17:487-97

[38] Virolle T,Baron V,Mercola D,de Belle I.The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling..Nat Cell Biol2001;3:1124-8

[39] Shen N,Wang JD,Qiao L,Xue B,Zhou XJ,Ning W.Cigarette smoke-induced pulmonary inflammatory responses are mediated by EGR-1/GGPPS/MAPK signaling..Am J Pathol2011;178:110-8 PMCID:PMC3069843

[40] Yu X,Zhang ML,Wang C,Liu C,Gao X,Li CJ.Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in mice..EMBO J2011;30:3754-65 PMCID:PMC3173797

[41] Weng K,Xu AG,Somel M.Mechanisms of dietary response in mice and primates: a role for EGR1 in regulating the reaction to human-specific nutritional content..PLoS One2012;7:e43915 PMCID:PMC3427207

[42] McMullen MR,Wang Q,Croniger CM.Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice..Gastroenterology2005;128:2066-76 PMCID:PMC1959407

[43] Song H,Wu J,Chu Q.White pitaya (hylocereus undatus) juice attenuates insulin resistance and hepatic steatosis in diet-induced obese mice..PLoS One2016;11:e0149670 PMCID:PMC4767368

[44] Ference BA,Graham I,Packard CJ,Hegele RA,Raal FJ,Watts GF,Fazio S,Masana L,Nordestgaard BG,Taskinen MR,Landmesser U,Wiklund O,Chapman MJ.Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel..Eur Heart J2017;38:2459-72

[45] Li T.Regulation of bile acid and cholesterol metabolism by PPARs..PPAR Res2009;2009:501739 PMCID:PMC2712638

[46] Madison BB.Srebp2: a master regulator of sterol and fatty acid synthesis..J Lipid Res2016;57:333-5 PMCID:PMC4766982

[47] Sanchez-Infantes D,Elks CM,Gimble JM,Ferrante AW,Stephens JM.Oncostatin m is produced in adipose tissue and is regulated in conditions of obesity and type 2 diabetes..J Clin Endocrinol Metab2014;99:E217-25 PMCID:PMC3913819

[48] Zhou Y,Abidi P,Thiel G.Blockage of oncostatin M-induced LDL receptor gene transcription by a dominant-negative mutant of C/EBPbeta..Biochem J2006;397:101-8 PMCID:PMC1479763

[49] Zhang F,Li C,Liu J.Identification of Egr1 as the oncostatin M-induced transcription activator that binds to sterol-independent regulatory element of human LDL receptor promoter..J Lipid Res2002;43:1477-85

[50] Taub R.Liver regeneration: from myth to mechanism..Nat Rev Mol Cell Biol2004;5:836-47

[51] Song Z,Ng IC,Yang YA.Mechanosensing in liver regeneration..Semin Cell Dev Biol2017;

[52] Tao Y,Chen E.Liver Regeneration: Analysis of the Main Relevant Signaling Molecules..Mediators Inflamm2017;2017:4256352 PMCID:PMC5602614

[53] Bohm F,Speicher T.Regulation of liver regeneration by growth factors and cytokines..EMBO Mol Med2010;2:294-305 PMCID:PMC3377328

[54] Dooley S.TGF-beta in progression of liver disease..Cell Tissue Res2012;347:245-56 PMCID:PMC3250614

[55] Sacilotto N,Riffo-Campos AL,Hibbitt O,Lopez C,Franco L.Growth arrest specific 1 (Gas1) gene overexpression in liver reduces the in vivo progression of murine hepatocellular carcinoma and partially restores gene expression levels..PLoS One2015;10:e0132477 PMCID:PMC4498802

[56] Biesiada E,Chorazy M.Expression of c-jun and Egr-1 genes in rat liver in response to partial hepatectomy, and injection of turpentine..Cell Biol Int Rep1992;16:53-62

[57] Peng Y,Ramirez S,Taub R.Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Egr-1 activation is an early event in liver regeneration..J Biol Chem1999;274:4513-20

[58] Liao Y,Shteyer E,Hruz PW.Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice..J Biol Chem2004;279:43107-16

[59] McKee SC,Sabourin LA.Regulation of expression of early growth response transcription factors in rat primary cortical neurons by extracellular ATP..Brain Res2006;1088:1-11

[60] Tackett BC,Mei Y,Cheruvu S,Hernandez-Garcia A,Karpen SJ.P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy..Am J Physiol Gastrointest Liver Physiol2014;307:G1073-87 PMCID:PMC4254960

[61] Greenbaum LE,Cressman DE,Ciliberto G,Taub R.CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy..J Clin Invest1998;102:996-1007 PMCID:PMC508965

[62] Li W,Leu JI,Ciliberto G.Global changes in interleukin-6-dependent gene expression patterns in mouse livers after partial hepatectomy..Hepatology2001;33:1377-86

[63] Lai S,Zhao D,Chen W,Yu D,Pan F,Li C.Regulation of mice liver regeneration by early growth response-1 through the GGPPS/RAS/MAPK pathway..Int J Biochem Cell Biol2015;64:147-54

[64] Donohue TMJr,Trambly CS,Thomes PG,Davis JS.Early growth response-1 contributes to steatosis development after acute ethanol administration..Alcohol Clin Exp Res2012;36:759-67 PMCID:PMC3297709

[65] Subrata LS,Olynyk JK,Quail EA.Hepatic expression of the tumor necrosis factor family member lymphotoxin-beta is regulated by interleukin (IL)-6 and IL-1beta: transcriptional control mechanisms in oval cells and hepatoma cell lines..Liver Int2005;25:633-46

[66] Mueller L,Meyer J,Goettsche J,Rogiers X.The induction of the immediate-early-genes Egr-1, PAI-1 and PRL-1 during liver regeneration in surgical models is related to increased portal flow..J Hepatol2002;37:606-12

[67] Pritchard MT.Hepatic fibrosis is enhanced and accompanied by robust oval cell activation after chronic carbon tetrachloride administration to Egr-1-deficient mice..Am J Pathol2010;176:2743-52 PMCID:PMC2877836

[68] Bryant M,Houston P,Campbell CJ.Tissue repair with a therapeutic transcription factor..Hum Gene Ther2000;11:2143-58

[69] Haas TL,Davis SJ,Madri JA.Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium..J Biol Chem1999;274:22679-85

[70] Pritchard MT.Identifying novel targets for treatment of liver fibrosis: what can we learn from injured tissues which heal without a scar?.Curr Drug Targets2015;16:1332-46 PMCID:PMC4838187

[71] Alexander D,Meyringer R,Gay S,Aicher WK.Transcription factor Egr-1 activates collagen expression in immortalized fibroblasts or fibrosarcoma cells..Biol Chem2002;383:1845-53

[72] Chen WN,Leong AL,Teng SW.Expression of integrated hepatitis B virus X variants in human hepatocellular carcinomas and its significance..Biochem Biophys Res Commun2000;276:885-92

[73] Xie Y,Dorko K,Schmitt TM,Jaeschke H.Mechanisms of acetaminophen-induced cell death in primary human hepatocytes..Toxicol Appl Pharmacol2014;279:266-74 PMCID:PMC4171351

[74] Peng WX,Ge L,Zhang CL,Xu M,Jin J.Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells..Exp Cell Res2016;340:62-70

[75] Watelet J,Bressenot A,Larrey D.Toxicity of chronic paracetamol ingestion..Aliment Pharmacol Ther2007;26:1543-4; author reply 1545-6

[76] Pang C,Sheng Y,Wei H,Ji L.Caffeic acid attenuated acetaminophen-induced hepatotoxicity by inhibiting ERK1/2-mediated early growth response-1 transcriptional activation..Chem Biol Interact2016;260:186-95

[77] Bai Q,Sheng Y,Shi L,Wang Z.Long-term acetaminophen treatment induced liver fibrosis in mice and the involvement of Egr-1..Toxicology2017;382:47-58

[78] Gitenay D.Is EGR1 a potential target for prostate cancer therapy?.Future Oncol2009;5:993-1003 PMCID:PMC2776080

[79] Yuan S,Cheng J,Zhou S,Shen L,Wang S.Age-associated up-regulation of EGR1 promotes granulosa cell apoptosis during follicle atresia in mice through the NF-kappaB pathway..Cell Cycle2016;15:2895-905 PMCID:PMC5105915

[80] Shareef MM,Burikhanov R,Satishkumar S,Mohiuddin M,Ahmed MM.Role of tumor necrosis factor-alpha and TRAIL in high-dose radiation-induced bystander signaling in lung adenocarcinoma..Cancer Res2007;67:11811-20

[81] Wang F,Salem N,Lee Z.Cross-species hybridization of woodchuck hepatitis viral infection-induced woodchuck hepatocellular carcinoma using human, rat and mouse oligonucleotide microarrays..J Gastroenterol Hepatol2009;24:605-17

[82] Choi EJ,Kim MS,Lee SH.Putative tumor suppressor genes EGR1 and BRSK1 are mutated in gastric and colorectal cancers..Oncology2016;91:289-94

[83] Lu Z,Wang Z.Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion..Cancer Cell2003;4:499-515

[84] Engelman JA,Razani B,Lisanti MP.p42/44 MAP kinase-dependent and -independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity..J Biol Chem1999;274:32333-41

[85] Dhillon AS,Rath O.MAP kinase signalling pathways in cancer..Oncogene2007;26:3279-90

[86] Berger E,Vidal H.Gene network analysis leads to functional validation of pathways linked to cancer cell growth and survival..Biotechnol J2012;7:1395-404

[87] Yang W,Li XY,Cao JP.Anti-tumor effect of 125I-UdR in combination with Egr-1 promoter-based IFNgamma gene therapy in vivo..Radiat Environ Biophys2010;49:705-14

[88] Hao MW,Liu YF,Wu MY.Transcription factor EGR-1 inhibits growth of hepatocellular carcinoma and esophageal carcinoma cell lines..World J Gastroenterol2002;8:203-7 PMCID:PMC4658351

[89] Park SE,Hossain MA,Kim MN,Park YC,Kim GY,Kim ND.A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells..Cancer Lett2008;270:77-86

[90] Yu J,Saito K,Arimura Y,Ke Y,Mercola D,Adamson E.PTEN regulation by Akt-EGR1-ARF-PTEN axis..EMBO J2009;28:21-33 PMCID:PMC2633077

[91] Tian H,Li H,Hou H,Jiang G,Cui Y,Li J.Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma..Hepatology2014;59:1459-70

[92] Wang L,Wang X,Zhao L,He K,Song T,Huang C.EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway..Oncotarget2016;7:45302-16 PMCID:PMC5216724

[93] Lee KH.Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells..Clin Exp Metastasis2009;26:685-92

[94] Archer KJ,David K,Bornstein K.Identifying genes for establishing a multigenic test for hepatocellular carcinoma surveillance in hepatitis C virus-positive cirrhotic patients..Cancer Epidemiol Biomarkers Prev2009;18:2929-32 PMCID:PMC2783293

[95] Ma Y,Huang Q,Wei W.GRK2 overexpression inhibits IGF1-induced proliferation and migration of human hepatocellular carcinoma cells by downregulating EGR1..Oncol Rep2016;35:3068-74

[96] Peng WX,Liu XJ,Xu N,Wang YQ.Hypoxia stabilizes microtubule networks and decreases tumor cell chemosensitivity to anticancer drugs through Egr-1..Anat Rec (Hoboken).2010;293:414-20

[97] Chang Y,He X,Li C,Nace G,Lin J.miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions..Gastroenterology2012;143:177-87.e8

[98] Toshima T,Matsumoto Y,Ikegami T,Soejima Y,Maehara Y.Autophagy enhances hepatocellular carcinoma progression by activation of mitochondrial beta-oxidation..J Gastroenterol2014;49:907-16

[99] Guo XL,Sun K,Liu Y,Zhao QD,Deng WJ,Wu MC.Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma..J Mol Med (Berl).2013;91:473-83 PMCID:PMC3611041