Epigenetics override pro-inflammatory PTGS transcriptomic signature towards selective hyperactivation of PGE 2 in colorectal cancer

Clinical Epigenetics

Miguel A. Peinado⁴  Victor Moreno⁶  Lisardo Boscá¹  Llorenç Coll-Mulet⁴  Susanna Aussó⁵  Patricia Prieto¹  Laia Paré⁵  Anna Díez-Villanueva⁴  Mar Muñoz⁴  Joaquin Custodio³  Inês Cebola² 

[1] Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain;Current address: Department of Medicine, Imperial College London, London, UK;Current address: Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;Institute of Predictive and Personalized Medicine of Cancer (IMPPC, Ctra Can Ruti, Cami de les Escoles, Badalona 08916, Spain;Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERESP, Hospitalet de Llobregat, Barcelona, Spain;Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain

关键词: Prostaglandins;    Inflammation;    Prostanoids;    COX pathway;    Gene expression;    DNA methylation;   

Others  :  1221396
DOI  :  10.1186/s13148-015-0110-4

 received in 2015-01-09, accepted in 2015-07-06,  发布年份 2015

【 摘 要 】

Background

Misregulation of the PTGS (prostaglandin endoperoxide synthase, also known as cyclooxygenase or COX) pathway may lead to the accumulation of pro-inflammatory signals, which constitutes a hallmark of cancer. To get insight into the role of this signaling pathway in colorectal cancer (CRC), we have characterized the transcriptional and epigenetic landscapes of the PTGS pathway genes in normal and cancer cells.

Results

Data from four independent series of CRC patients (502 tumors including adenomas and carcinomas and 222 adjacent normal tissues) and two series of colon mucosae from 69 healthy donors have been included in the study. Gene expression was analyzed by real-time PCR and Affymetrix U219 arrays. DNA methylation was analyzed by bisulfite sequencing, dissociation curves, and HumanMethylation450K arrays. Most CRC patients show selective transcriptional deregulation of the enzymes involved in the synthesis of prostanoids and their receptors in both tumor and its adjacent mucosa. DNA methylation alterations exclusively affect the tumor tissue (both adenomas and carcinomas), redirecting the transcriptional deregulation to activation of prostaglandin E ₂(PGE ₂ ) function and blockade of other biologically active prostaglandins. In particular, PTGIS, PTGER3, PTGFR, and AKR1B1 were hypermethylated in more than 40 % of all analyzed tumors.

Conclusions

The transcriptional and epigenetic profiling of the PTGS pathway provides important clues on the biology of the tumor and its microenvironment. This analysis renders candidate markers with potential clinical applicability in risk assessment and early diagnosis and for the design of new therapeutic strategies.

【 授权许可】

   
2015 Cebola et al.

【 图 表 】

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【 参考文献 】

• [1]Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature 2008, 454:436-44.
• [2]Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009, 30:1073-81.
• [3]Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell 2010, 140:883-99.
• [4]Aggarwal BB, Vijayalekshmi RV, Sung B: Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009, 15:425-30.
• [5]Cathcart MC, Lysaght J, Pidgeon GP: Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention. Cancer Metastasis Rev 2011, 30:363-85.
• [6]Greenhough A, Smartt HJM, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al.: The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009, 30:377-86.
• [7]Wang D, Dubois RN: The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 2010, 29:781-8.
• [8]Coghill AE, Newcomb PA, Poole EM, Hutter CM, Makar KW, Duggan D, et al.: Genetic variation in inflammatory pathways is related to colorectal cancer survival. Clin Cancer Res 2011, 17:7139-47.
• [9]Resler AJ, Makar KW, Heath L, Whitton J, Potter JD, Poole EM, et al.: Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry. Carcinogenesis 2014, 35(9):2121-6.
• [10]Poole EM, Hsu L, Xiao L, Kulmacz RJ, Carlson CS, Rabinovitch PS, et al.: Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 2010, 19:547-57.
• [11]Cox DG, Pontes C, Guino E, Navarro M, Osorio A, Canzian F, et al.: Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 2004, 91:339-43.
• [12]Rigas B, Goldman IS, Levine L: Altered eicosanoid levels in human colon cancer. J Lab Clin Med 1993, 122:518-23.
• [13]Pugh S, Thomas GA: Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut 1994, 35:675-8.
• [14]Ogino S, Kirkner GJ, Nosho K, Irahara N, Kure S, Shima K, et al.: Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res 2008, 14:8221-7.
• [15]Tsujii M, Kawano S, DuBois RN: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A 1997, 94:3336-40.
• [16]Kunzmann AT, Murray LJ, Cardwell CR, McShane CM, McMenamin UC, Cantwell MM: PTGS2 (Cyclooxygenase-2) expression and survival among colorectal cancer patients: a systematic review. Cancer Epidemiol Biomarkers Prev 2013, 22:1490-7.
• [17]Kurtova AV, Xiao J, Mo Q, Pazhanisamy S, Krasnow R, Lerner SP et al. Blocking PGE-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature. 2014;517:209–13.
• [18]Tougeron D, Sha D, Manthravadi S, Sinicrope FA: Aspirin and colorectal cancer: back to the future. Clin Cancer Res 2014, 20:1087-94.
• [19]Sahin IH, Hassan MM, Garrett CR: Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: current state-of-the science. Cancer Lett 2014, 345:249-57.
• [20]Thun MJ, Jacobs EJ, Patrono C: The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012, 9:259-67.
• [21]Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al.: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012, 367:1596-606.
• [22]Ulrich CM, Bigler J, Potter JD: Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006, 6:130-40.
• [23]Ng K, Meyerhardt JA, Chan AT, Sato K, Chan JA, Niedzwiecki D, et al.: Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 2015, 107:345.
• [24]Din FV, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, et al.: Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 2010, 59:1670-9.
• [25]Patrignani P, Capone ML, Tacconelli S: NSAIDs and cardiovascular disease. Heart 2008, 94:395-7.
• [26]Colussi D, Brandi G, Bazzoli F, Ricciardiello L: Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci 2013, 14:16365-85.
• [27]Carmona FJ, Esteller M: Epigenomics of human colon cancer. Mutat Res 2010, 693:53-60.
• [28]Bardhan K, Liu K: Epigenetics and colorectal cancer pathogenesis. Cancers (Basel) 2013, 5:676-713.
• [29]Esteller M: Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 2007, 8:286-98.
• [30]Jones PA, Baylin SB: The epigenomics of cancer. Cell 2007, 128:683-92.
• [31]Cebola I, Peinado MA: Epigenetic deregulation of the COX pathway in cancer. Prog Lipid Res 2012, 51:301-13.
• [32]Harris RE: Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell Biochem 2007, 42:93-126.
• [33]Karnes WE Jr, Shattuck-Brandt R, Burgart LJ, DuBois RN, Tester DJ, Cunningham JM, et al.: Reduced COX-2 protein in colorectal cancer with defective mismatch repair. Cancer Res 1998, 58:5473-7.
• [34]Sinicrope FA, Lemoine M, Xi L, Lynch PM, Cleary KR, Shen Y, et al.: Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis colorectal cancers relative to sporadic cancers. Gastroenterology 1999, 117:350-8.
• [35]Frigola J, Muñoz M, Clark SJ, Moreno V, Capella G, Peinado MA: Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy. Oncogene 2005, 24:7320-6.
• [36]Luo Y, Wong CJ, Kaz AM, Dzieciatkowski S, Carter KT, Morris SM, et al.: Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 2014, 147:418-29.
• [37]Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, et al.: DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002, 416:552-6.
• [38]Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 2004, 10:789-99.
• [39]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-74.
• [40]Toyota M, Shen L, Ohe-Toyota M, Hamilton SR, Sinicrope FA, Issa JP: Aberrant methylation of the cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res 2000, 60:4044-8.
• [41]de Maat MFG, van de Velde CJH, Umetani N, de Heer P, Putter H, van Hoesel AQ, et al.: Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer. J Clin Oncol 2007, 25:4887-94.
• [42]Shoji Y, Takahashi M, Kitamura T, Watanabe K, Kawamori T, Maruyama T, et al.: Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development. Gut 2004, 53:1151-8.
• [43]Gustafsson A, Hansson E, Kressner U, Nordgren S, Andersson M, Lonnroth C, et al.: Prostanoid receptor expression in colorectal cancer related to tumor stage, differentiation and progression. Acta Oncol 2007, 46:1107-12.
• [44]Kropotova ES, Tychko RA, Zinov'eva OL, Zyrianova AF, Khankin SL, Cherkes VL, et al.: Downregulation of AKR1B10 gene expression in colorectal cancer. Mol Biol (Mosk) 2010, 44:243-50.
• [45]Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E, et al.: Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 2006, 38:149-53.
• [46]Tsujii M: Cyclooxygenase, cancer stem cells and DNA methylation play important roles in colorectal carcinogenesis. Digestion 2013, 87:12-6.
• [47]Xia D, Wang D, Kim SH, Katoh H, DuBois RN: Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat Med 2012, 18:224-6.
• [48]Nakanishi M, Perret C, Meuillet EJ, Rosenberg DW: Non-cell autonomous effects of targeting inducible PGE2 synthesis during inflammation-associated colon carcinogenesis. Carcinogenesis 2015, 36:478-86.
• [49]Wang D, DuBois RN: Cyclooxygenase 2-derived prostaglandin E2 regulates the angiogenic switch. Proc Natl Acad Sci U S A 2004, 101:415-6.
• [50]Zuo X, Shureiqi I: Eicosanoid profiling in colon cancer: emergence of a pattern. Prostaglandins Other Lipid Mediat 2013, 104-105:139-43.
• [51]Chandramouli A, Onyeagucha BC, Mercado-Pimentel ME, Stankova L, Shahin NA, LaFleur BJ, et al.: MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers. Cancer Biol Ther 2012, 13:175-83.
• [52]Katoh H, Hosono K, Ito Y, Suzuki T, Ogawa Y, Kubo H, et al.: COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems. Am J Pathol 2010, 176:1469-83.
• [53]Kubo H, Hosono K, Suzuki T, Ogawa Y, Kato H, Kamata H, et al.: Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis. Biomed Pharmacother 2010, 64:101-6.
• [54]Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R: Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol 2014, 20:6055-72.
• [55]Barrow TM, Michels KB: Epigenetic epidemiology of cancer. Biochem Biophys Res Commun 2014, 455:70-83.
• [56]Coppede F: The role of epigenetics in colorectal cancer. Expert Rev Gastroenterol Hepatol 2014, 8:935-48.
• [57]Ogino S, Lochhead P, Chan AT, Nishihara R, Cho E, Wolpin BM, et al.: Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease. Mod Pathol 2013, 26:465-84.
• [58]Sanz-Pamplona R, Berenguer A, Cordero D, Mollevi DG, Crous-Bou M, Sole X, et al.: Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer. Mol Cancer 2014, 13:46. BioMed Central Full Text
• [59]Worm J, Aggerholm A, Guldberg P: In-tube DNA methylation profiling by fluorescence melting curve analysis. Clin Chem 2001, 47:1183-9.