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Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that couples with cyclooxygenase-2 (COX-2) for the production of PGE2. Although COX-2 is known to mediate the growth and progression of several human cancers including hepatocellular carcinoma (HCC), the role of mPGES-1 in hepatocarcinogenesis is not well established. This study provides novel evidence for a key role of mPGES-1 in HCC growth and progression. Forced overexpression of mPGES-1 in two HCC cell lines (Hep3B and Huh7) increased tumor cell growth, clonogenic formation, migration and invasion, whereas knockdown of mPGES-1 inhibited these parameters, in vitro. In a mouse tumor xenograft model, mPGES-1-overexpressed cells formed palpable tumors at earlier time points and developed larger tumors when compared with the control (P<0.01); in contrast, mPGES-1 knockdown delayed tumor development and reduced tumor size (P<0.01). Mechanistically, mPGES-1-induced HCC cell proliferation, invasion and migration involve PGE2 production and activation of early growth response 1 (EGR1) and β-catenin. Specifically, mPGES-1-derived PGE2 induces the formation of EGR1-β-catenin complex, which interacts with T-cell factor 4/lymphoid enhancer factor 1 transcription factors and activates the expression of β-catenin downstream genes. Our findings depict a novel crosstalk between mPGES-1/PGE2 and EGR1/β-catenin signaling that is critical for hepatocarcinogenesis.

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Abbreviations

COX-2:

cyclooxygenase-2

GSK-3β:

glycogen synthase kinase 3 beta

HCC:

hepatocellular carcinoma

LEF:

lymphoid enhancer factor

mPGES-1:

microsomal prostaglandin E synthase-1

PGE2:

prostaglandin E2

SUMO:

small ubiquitin-like modifier

TCF:

T-cell factor

References

  • Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG et al. (2001). Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 7: 1410–1418.

    CAS  Google Scholar 

  • Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A et al. (2006). A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131: 1674–1682.

    Article  CAS  Google Scholar 

  • Bijur GN, Jope RS . (2001). Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 276: 37436–37442.

    Article  CAS  Google Scholar 

  • Henderson BR . (2000). Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol 2: 653–660.

    Article  CAS  Google Scholar 

  • Branda M, Wands JR . (2006). Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology 43: 891–902.

    Article  CAS  Google Scholar 

  • Caspi M, Zilberberg A, Eldar-Finkelman H, Rosin-Arbesfeld R . (2008). Nuclear GSK-3beta inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. Oncogene 27: 3546–3555.

    Article  CAS  Google Scholar 

  • Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS . (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310: 1504–1510.

    Article  CAS  Google Scholar 

  • Cheng AS, Chan HL, To KF, Leung WK, Chan KK, Liew CT et al. (2004). Cyclooxygenase-2 pathway correlates with vascular endothelial growth factor expression and tumor angiogenesis in hepatitis B virus-associated hepatocellular carcinoma. Int J Oncol 24: 853–860.

    CAS  Google Scholar 

  • Clevers H . (2006). Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.

    Article  CAS  Google Scholar 

  • Couzin J . (2004). Clinical trials. Nail-biting time for trials of COX-2 drugs. Science 306: 1673–1675.

    Article  CAS  Google Scholar 

  • Danesch U, Weber PC, Sellmayer A . (1994). Arachidonic acid increases c-fos and Egr-1 mRNA in 3T3 fibroblasts by formation of prostaglandin E2 and activation of protein kinase C. J Biol Chem 269: 27258–27263.

    CAS  Google Scholar 

  • Diehl JA, Cheng M, Roussel MF, Sherr CJ . (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12: 3499–3511.

    Article  CAS  Google Scholar 

  • Dihlmann S, Kloor M, Fallsehr C, von Knebel Doeberitz M . (2005). Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis 26: 1503–1512.

    Article  CAS  Google Scholar 

  • El-Serag HB, Mason AC . (1999). Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340: 745–750.

    Article  CAS  Google Scholar 

  • El-Serag HB . (2004). Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127: S27–S34.

    Article  Google Scholar 

  • Farazi PA, DePinho RA . (2006). Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6: 674–687.

    Article  CAS  Google Scholar 

  • Giles RH, van Es JH, Clevers H . (2003). Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653: 1–24.

    CAS  Google Scholar 

  • Gitenay DBV . (2009). Is EGR1 a potential target for prostate cancer therapy? Future Oncol 5: 993–1003.

    Article  CAS  Google Scholar 

  • Gordon MD, Nusse R . (2006). Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281: 22429–22433.

    Article  CAS  Google Scholar 

  • Grosser T, Fries S, FitzGerald GA . (2006). Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116: 4–15.

    Article  CAS  Google Scholar 

  • Han C, Michalopoulos GK, Wu T . (2006). Prostaglandin E(2) receptor EP(1) transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J Cell Physiol 207: 261–270.

    Article  CAS  Google Scholar 

  • Hanaka H, Pawelzik SC, Johnsen JI, Rakonjac M, Terawaki K, Rasmuson A et al. (2009). Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc Natl Acad Sci USA 106: 18757–18762.

    Article  CAS  Google Scholar 

  • Hoppler S, Kavanagh CL . (2007). Wnt signalling: variety at the core. J Cell Sci 120: 385–393.

    Article  CAS  Google Scholar 

  • Itoh K, Brott BK, Bae GU, Ratcliffe MJ, Sokol SY . (2005). Nuclear localization is required for dishevelled function in Wnt/beta-catenin signaling. J Biol 4: 3.

    Article  Google Scholar 

  • Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B . (1999). Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci USA 96: 7220–7225.

    Article  CAS  Google Scholar 

  • Kamei D, Murakami M, Sasaki Y, Nakatani Y, Majima M, Ishikawa Y et al. (2010). Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis. Biochem J 425: 361–371.

    Article  CAS  Google Scholar 

  • Kang YJ, Mbonye UR, DeLong CJ, Wada M, Smith WL . (2007). Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res 46: 108–125.

    Article  CAS  Google Scholar 

  • Kapoor M, Kojima F, Qian M, Yang L, Crofford LJ . (2007). Microsomal prostaglandin E synthase-1 deficiency is associated with elevated peroxisome proliferator-activated receptor gamma: regulation by prostaglandin E2 via the phosphatidylinositol 3-kinase and Akt pathway. J Biol Chem 282: 5356–5366.

    Article  CAS  Google Scholar 

  • Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K et al. (1999). Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 29: 688–696.

    Article  CAS  Google Scholar 

  • Kondo M, Yamamoto H, Nagano H, Okami J, Ito Y, Shimizu J et al. (1999). Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res 5: 4005–4012.

    CAS  Google Scholar 

  • Lee KH KJ . (2009). Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells. Clin Exp Metastasis 26: 685–692.

    Article  Google Scholar 

  • Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T . (2003). Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology 38: 756–768.

    Article  CAS  Google Scholar 

  • Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T . (2008). Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. Cancer Res 68: 553–560.

    Article  CAS  Google Scholar 

  • Lim K, Han C, Dai Y, Shen M, Wu T . (2009). Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther 8: 3046–3055.

    Article  CAS  Google Scholar 

  • Llovet JM, Bruix J . (2008). Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48: 1312–1327.

    Article  CAS  Google Scholar 

  • Ma J, Ren Z, Ma Y, Xu L, Zhao Y, Zheng C et al. (2009). Targeted knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated invasion of prostate cancer cells through suppressing EGR-1/NF-kappaB synergy. J Biol Chem 284: 34600–34606.

    Article  CAS  Google Scholar 

  • Merle P, de la Monte S, Kim M, Herrmann M, Tanaka S, Von Dem Bussche A et al. (2004). Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 127: 1110–1122.

    Article  CAS  Google Scholar 

  • Monga SP . (2006). Hepatic adenomas: presumed innocent until proven to be beta-catenin mutated. Hepatology 43: 401–404.

    Article  CAS  Google Scholar 

  • Moon RT, Kohn AD, De Ferrari GV, Kaykas A . (2004). WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5: 691–701.

    Article  CAS  Google Scholar 

  • Moon Y, Lee M, Yang H . (2007). Involvement of early growth response gene 1 in the modulation of microsomal prostaglandin E synthase 1 by epigallocatechin gallate in A549 human pulmonary epithelial cells. Biochem Pharmacol 73: 125–135.

    Article  CAS  Google Scholar 

  • Morisco CSK, Hardt SE, Lee Y, Vatner SF, Sadoshima J. . (2001). Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes. J Biol Chem 276: 28586–28597.

    Article  CAS  Google Scholar 

  • Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F et al. (2000). Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275: 32783–32792.

    Article  CAS  Google Scholar 

  • Murakami M, Kudo I . (2006). Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr Pharm Des 12: 943–954.

    Article  CAS  Google Scholar 

  • Ngiam N, Peltekova V, Engelberts D, Otulakowski G, Post M, Kavanagh BP . (2010). Early growth response-1 worsens ventilator-induced lung injury by up-regulating prostanoid synthesis. Am J Respir Crit Care Med 181: 947–956.

    Article  CAS  Google Scholar 

  • Parra E, Ortega A, Saenz L . (2009). Down-regulation of Egr-1 by siRNA inhibits growth of human prostate carcinoma cell line PC-3. Oncol Rep 22: 1513–1518.

    CAS  Google Scholar 

  • Philipp-Staheli J, Kim KH, Payne SR, Gurley KE, Liggitt D, Longton G et al. (2002). Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell 1: 355–368.

    Article  Google Scholar 

  • Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H et al. (2001). Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res 7: 1325–1332.

    CAS  Google Scholar 

  • Saegusa M, Hashimura M, Kuwata T, Hamano M, Okayasu I . (2004). Beta-catenin simultaneously induces activation of the p53-p21WAF1 pathway and overexpression of cyclin D1 during squamous differentiation of endometrial carcinoma cells. Am J Pathol 164: 1739–1749.

    Article  CAS  Google Scholar 

  • Saegusa M, Hashimura M, Kuwata T, Hamano M, Watanabe J, Kawaguchi M et al. (2008). Transcription factor Egr1 acts as an upstream regulator of beta-catenin signalling through up-regulation of TCF4 and p300 expression during trans-differentiation of endometrial carcinoma cells. J Pathol 216: 521–532.

    Article  CAS  Google Scholar 

  • Samuelsson B, Morgenstern R, Jakobsson PJ . (2007). Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 59: 207–224.

    Article  CAS  Google Scholar 

  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T et al. (2000). AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24: 245–250.

    Article  CAS  Google Scholar 

  • Shao J, Jung C, Liu C, Sheng H . (2005). Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. J Biol Chem 280: 26565–26572.

    Article  CAS  Google Scholar 

  • Shiota G, Okubo M, Noumi T, Noguchi N, Oyama K, Takano Y et al. (1999). Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology 46: 407–412.

    CAS  Google Scholar 

  • Smith WL, DeWitt DL, Garavito RM . (2000). Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69: 145–182.

    Article  CAS  Google Scholar 

  • Smith WL, Langenbach R . (2001). Why there are two cyclooxygenase isozymes. J Clin Invest 107: 1491–1495.

    Article  CAS  Google Scholar 

  • Stichtenoth DO, Thorén S, Bian H, Peters-Golden M, Jakobsson PJ, Crofford LJ. . (2001). Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 167: 469–474.

    Article  CAS  Google Scholar 

  • Subbaramaiah K, Yoshimatsu K, Scherl E, Das KM, Glazier KD, Golijanin D et al. (2004). Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1. J Biol Chem 279: 12647–12658.

    Article  CAS  Google Scholar 

  • Takii Y, Abiru S, Fujioka H, Nakamura M, Komori A, Ito M et al. (2007). Expression of microsomal prostaglandin E synthase-1 in human hepatocelluar carcinoma. Liver Int 27: 989–996.

    Article  CAS  Google Scholar 

  • Tetsu O, McCormick F . (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426.

    Article  CAS  Google Scholar 

  • Thiel G, Mayer SI, Muller I, Stefano L, Rossler OG . (2010). Egr-1-A Ca(2+)-regulated transcription factor. Cell Calcium 47: 397–403.

    Article  CAS  Google Scholar 

  • Thompson MD, Monga SP . (2007). WNT/beta-catenin signaling in liver health and disease. Hepatology 45: 1298–1305.

    Article  CAS  Google Scholar 

  • Thoren S, Weinander R, Saha S, Jegerschold C, Pettersson PL, Samuelsson B et al. (2003). Human microsomal prostaglandin E synthase-1: purification, functional characterization, and projection structure determination. J Biol Chem 278: 22199–22209.

    Article  CAS  Google Scholar 

  • Vanchieri C . (2004). Vioxx withdrawal alarms cancer prevention researchers. J Natl Cancer Inst 96: 1734–1735.

    Article  Google Scholar 

  • Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T et al. (2001). The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol 3: 1124–1128.

    Article  CAS  Google Scholar 

  • Wu T . (2006). Cyclooxygenase-2 in hepatocellular carcinoma. Cancer Treat Rev 32: 28–44.

    Article  CAS  Google Scholar 

  • Yu J, Zhang SS, Saito K, Williams S, Arimura Y, Ma Y et al. (2009). PTEN regulation by Akt-EGR1-ARF-PTEN axis. EMBO J 28: 21–33.

    Article  Google Scholar 

  • Zucman-Rossi J, Jeannot E, Van Nhieu JT, Scoazec JY, Guettier C, Rebouissou S et al. (2006). Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 43: 515–524.

    Article  CAS  Google Scholar 

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Acknowledgements

This work is supported by the National Institutes of Health grants CA106280, CA102325, CA134568 and DK077776 (to TW) and CA137729 (to CH).

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Lu, D., Han, C. & Wu, T. Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis. Oncogene 31, 842–857 (2012). https://doi.org/10.1038/onc.2011.287

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