Epigenetic regulation of gene expression and M2 macrophage polarization as new potential omega-3 polyunsaturated fatty acid targets in colon inflammation and cancer

Expert Opinion on Therapeutic Targets

Volumn 20, Issue 7, 2016, Pages 843-858

  Serini, Simona ^a   Ottes Vasconcelos, Renata ^a,b   Fasano, Elena ^a   Calviello, Gabriella ^a  

^a CATHOLIC UNIVERSITY   (Italy)

^b FEDERAL UNIVERSITY OF RIO GRANDE   (Brazil)

Author keywords

Cancer; colon; epigenetics; inflammation; macrophage polarization; omega 3 PUFA

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; BETA ARRESTIN 2; BIOLOGICAL MARKER; CALCIUM; CD59 ANTIGEN; CYCLOOXYGENASE 2; G PROTEIN COUPLED RECEPTOR; HISTONE H3; INTERLEUKIN 6; LIPOXIN; LIPOXYGENASE; MICRORNA; OMEGA 3 FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHOLIPID; PROSTAGLANDIN E2; PROSTAGLANDIN SYNTHASE; PROTEIN BCL 2; SATURATED FATTY ACID; SPHINGOLIPID; STEROL REGULATORY ELEMENT BINDING PROTEIN 1;

ANGIOGENESIS; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CALCIUM SIGNALING; CANCER GROWTH; CARCINOGENESIS; CARCINOGENIC ACTIVITY; CELL DIFFERENTIATION; CELL POLARITY; CELL PROLIFERATION; CELL SURVIVAL; CHROMATIN STRUCTURE; COLITIS; COLON CANCER; COLON MUCOSA; DIETARY INTAKE; DNA METHYLATION; ENZYME METABOLISM; EPIGENETICS; GENE EXPRESSION; GENETIC MANIPULATION; HISTONE ACETYLATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INNATE IMMUNITY; LIGAND BINDING; LIPID PEROXIDATION; LIPID RAFT; MACROPHAGE; NONHUMAN; OXIDATIVE STRESS; PHAGOCYTOSIS; PHENOTYPE; PROMOTER REGION; PROTEIN PHOSPHORYLATION; REVIEW; ANIMAL; COLONIC DISEASES; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; INFLAMMATION; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; PATHOLOGY;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; COLONIC DISEASES; EPIGENESIS, GENETIC; FATTY ACIDS, OMEGA-3; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATION; MACROPHAGES; MOLECULAR TARGETED THERAPY; NEOPLASMS;

EID: 84958541101     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2016.1139085     Document Type: Review

References (156)

1. F.A.Haggar, R.P.Boushey Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22:191–197.
2. G.Calviello, S.Serini, E.Piccioni ω-3 polyunsaturated fatty acids and the prevention of colorectal cancer: molecular mechanisms involved. Curr Med Chem. 2007;14:3059–3069.
3. P.C.Calder. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim Biophys Acta. 2015;1851:469–484.
4. K.Yang, H.Li, J.Dong, et al. Expression profile of polyunsaturated fatty acids in colorectal cancer. World J Gastroenterol. 2015;21:2405–2412.
5. P.C.Calder. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie. 2009;91:791–795.
6. G.S.Ranger. Current concepts in colorectal cancer prevention with cyclooxygenase inhibitors. Anticancer Res. 2014;34:6277–6282.
7. P.Guillem-Llobat, M.Dovizio, S.Alberti, et al. Platelets, cyclooxygenases, and colon cancer. Semin Oncol. 2014;41:385–396.
8. S.Temraz, D.Mukherji, A.Shamseddine. Potential targets for colorectal cancer prevention. Int J Mol Sci. 2013;14:17279–17303.
9. L.Fini, G.Piazzi, C.Ceccarelli, et al. Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in Apc(Min/+) mice. Clin Cancer Res. 2010;16:5703–5711.
10. N.Y.Song, H.K.Na, J.H.Baek, et al. Docosahexaenoic acid inhibits insulin-induced activation of sterol regulatory-element binding protein 1 and cyclooxygenase-2 expression through upregulation of SIRT1 in human colon epithelial cells. Biochem Pharmacol. 2014;92:142–148.
11. M.B.Petrik, M.F.McEntee, C.H.Chiu, et al. Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice. J Nutr. 2000;130:1153–1158.
12. K.H.Weylandt, S.Serini, Y.Q.Chen, et al. Omega-3 polyunsaturated fatty acids: the way forward in times of mixed evidence. Biomed Res Int. 2015;2015:143109.• This comprehensive review focalizes on the controversies existing at the moment among the outcomes of the published human studies investigating intervention with ω-3 PUFA in the field of cardiovascular, inflammatory and neoplastic diseases.
13. M.Anti, G.Marra, F.Armelao, et al. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology. 1992;103:883–891.• The first human intervention study to show the protective effect of ω-3 PUFA on the abnormally proliferating mucosa of patients at high risk for colon cancer.
14. E.D.Courtney, S.Matthews, C.Finlayson, et al. Eicosapentaenoic acid (EPA) reduces crypt cell proliferation and increases apoptosis in normal colonic mucosa in subjects with a history of colorectal adenomas. Int J Colorectal Dis. 2007;22:765–776.
15. M.Anti, F.Armelao, G.Marra, et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology. 1994;107:1709–1718.
16. Y.C.Huang, J.M.Jessup, R.A.Forse, et al. ω-3 fatty acids decrease colonic epithelial cell proliferation in high-risk bowel mucosa. Lipids. 1996;31(Suppl.):S313–S317.
17. H.P.Bartram, A.Gostner, W.Scheppach, et al. Effects of fish oil on rectal cell proliferation, mucosal fatty acids, and prostaglandin E2 release in healthy subjects. Gastroenterology. 1993;105:1317–1322.
18. J.Cheng, K.Ogawa, K.Kuriki, et al. Increased intake of ω-3 polyunsaturated fatty acids elevates the level of apoptosis in the normal sigmoid colon of patients polypectomized for adenomas/tumors. Cancer Lett. 2003;193:17–24.
19. A.J.Cockbain, M.Volpato, A.D.Race, et al. Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Gut. 2014;63:1760–1768.
20. G.K.Pot, G.Majsak-Newman, A.Geelen, et al. Fish consumption and markers of colorectal cancer risk: a multicenter randomized controlled trial. Am J Clin Nutr. 2009;90:354–361.
21. G.K.Pot, A.Geelen, G.Majsak-Newman, et al. Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies. J Nutr. 2010;140:371–376.
22. N.J.West, S.K.Clark, R.K.Phillips, et al. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010;59:918–925.•• The study demonstrates that the treatment with EPA free fatty acid has chemopreventive efficacy in a condition of high risk for colon cancer, and to a degree similar to that observed with selective cyclo-oxygenase-2 inhibitors.
23. E.J.Freireich, E.A.Gehan, D.P.Rall, et al. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep. 1966;50:219–244.
24. E.Fasano, S.Serini, A.Cittadini, et al. Long-Chain ω-3 PUFA against breast and prostate cancer: which are the appropriate doses for intervention studies in animals and humans?. Crit Rev Food Sci Nutr. 2015, Apr21 [Epub ahead of print] PMID: 25897862.•• This comprehensive review highlights that the effects of ω-3 PUFA are always obtained as the maximal increase in tissues incorporation (2-5 fold increase, comparable in humans and animals) is achieved, despite the different ranges of doses used in animal and clinical studies.
25. P.Bougnoux, N.Hajjaji, M.N.Ferrasson, et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer. 2009;101:1978–1985.
26. L.D.Yee, J.L.Lester, R.M.Cole, et al. Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition. Am J Clin Nutr. 2010;91:1185–1194.
27. G.Calviello, S.Serini, P.Palozza. ω-3 polyunsaturated fatty acids as signal transduction modulators and therapeutical agents in cancer. Curr Signal Transd T. 2006;1:255–271.
28. M.Gerber. Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies. Br J Nutr. 2012;107(Suppl):S228–S239.
29. Y.M.Dupertuis, M.M.Meguid, C.Pichard. Colon cancer therapy: new perspectives of nutritional manipulations using polyunsaturated fatty acids. Curr Opin Clin Nutr Metab Care. 2007;10:427–432.
30. R.A.Siddiqui, K.Harvey, W.Stillwell. Anticancer properties of oxidation products of docosahexaenoic acid. Chem Phys Lipids. 2008;153:47–56.
31. Z.Y.Chen, N.W.Istfan. Docosahexaenoic acid is a potent inducer of apoptosis in HT-29 colon cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2000;63:301–308.
32. G.Benais-Pont, Y.M.Dupertuis, M.P.Kossovsky, et al omega-3 polyunsaturated fatty acids and ionizing radiation: combined cytotoxicity on human colorectal adenocarcinoma cells. Nutrition. 2006;22:931–939.
33. J.Hofmanová, A.Vaculová, Z.Koubková, et al. Human fetal colon cells and colon cancer cells respond differently to butyrate and PUFAs. Mol Nutr Food Res. 2009;53(Suppl 1):S102–13.
34. H.F.Turk, R.S.Chapkin. Membrane lipid raft organization is uniquely modified by n-3 polyunsaturated fatty acids. Prostagl Leukot Essent Fatty Acids. 2013;88:43–47.
35. W.Stillwell, S.R.Wassall. Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids. 2003;126:1–27.
36. D.A.Brown, E.London. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000;275:17221–17224.
37. D.W.Ma, J.Seo, L.A.Davidson, et al. n-3 PUFAs alter caveolae lipid composition and resident protein localization in mouse colon. Faseb J. 2004;18:1040–1042.
38. D.W.Ma, J.Seo, K.C.Switzer, et al. n-3 PUFAs and membrane microdomains: a new frontier in bioactive lipid research. J Nutr Biochem. 2004;15:700–706.
39. Z.Liu, H.Li, X.Wu, et al. Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells. Oncogene. 2006;25:7680–7690.
40. -Y.-Y.Fan, L.H.Ly, R.Barhoumi, et al. Dietary docosahexaenoic acid suppresses T cell protein kinase C theta lipid raft recruitment and IL-2 production. J Immunol. 2004;173:6151–6160.
41. P.Habbel, K.H.Weylandt, K.Lichopoj, et al. Docosahexaenoic acid suppresses arachidonic acid-induced proliferation of LS-174T human colon carcinoma cells. World J Gastroenterol. 2009;15:1079–1084.
42. G.Furstenberger, P.Krieg, K.Muller-Decker, et al. What are cyclooxygenases and lipoxygenases doing in the driver’s seat of carcinogenesis? Int J Cancer. 2006;119:2247–2254.
43. G.Calviello, F.Di Nicuolo, S.Gragnoli, et al. n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and −2 and HIF-1alpha induction pathway. Carcinogenesis. 2004;25:2303–2310.
44. N.Arber, C.J.Eagle, J.Spicak, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885–895.
45. J.A.Baron. Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res. 2003;37:1–24.
46. M.M.Bertagnolli, C.J.Eagle, A.G.Zauber, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873–884.
47. H.E.Vonkeman, M.A.van de Laar. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum. 2010;39:294–312.
48. J.M.Park, Y.M.Han, M.Jeong, et al. Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage. J Gastroenterol. 2015;50:614–625.
49. C.D.Buckley, D.W.Gilroy, C.N.Serhan. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014;40:315–327.
50. B.D.Levy, C.B.Clish, B.Schmidt, et al. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2:612–619.
51. S.Hong, K.Gronert, P.R.Devchand, et al. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in antiinflammation. J Biol Chem. 2003;278:14677–14687.
52. M.Ricote, A.C.Li, T.M.Willson, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.
53. C.Cipollina. Endogenous generation and signaling actions of omega-3 fatty acid electrophilic derivatives. Biomed Res Int. 2015;2015:501792.• This is a comprehensive review article that examines the results of studies investigating the signaling activities of ω-3 PUFA electrophilic derivatives.
54. C.N.Serhan, N.A.Petasis. Resolvins and protectins in inflammation resolution. Chem Rev. 2011;111:5922–5943.
55. C.N.Serhan, R.Yang, K.Martinod, et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J Exp Med. 2009;206:15–23.
56. C.N.Serhan. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101.
57. S.Krishnamoorthy, A.Recchiuti, N.Chiang, et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci USA. 2010;107:1660–1665.
58. M.Herová, M.Schmid, C.Gemperle, et al. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J Immunol. 2015;194:2330–2337.
59. A.Recchiuti, S.Krishnamoorthy, G.Fredman, et al. MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits. Faseb J. 2011;25:544–560.•• The first study to describe the modulation of non-coding miRNA by an enzymatic-oxygenated derivative of DHA.
60. D.Y.Oh, J.M.Olefsky. Omega 3 fatty acids and GPR120. Cell Metab. 2012;15:564–565.
61. A.U.Hasan, K.Ohmori, K.Konishi, et al. Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2015;406:10–18.
62. H.Y.Chang, H.-N.Lee, W.Kim, et al. Docosahexaenoic acid induces M2 macrophage polarization through peroxisome proliferator-activated receptor γ activation. Life Sci. 2015;120:39–47.
63. D.-S.Im. Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs. Prog Lipid Res. 2012;51:232–237.
64. Y.Zhao, F.Calon, C.Julien, et al. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer’s disease models. PLoS One. 2011;6:e15816.
65. Y.-H.Yu, S.-C.Wu, W.T.Cheng, et al. The function of porcine PPARγ and dietary fish oil effect on the expression of lipid and glucose metabolism related genes. J Nutr Biochem. 2011;22:179–186.
66. L.Dubuquoy, C.Rousseaux, X.Thuru, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 2006;55:1341–1349.
67. W.Vanden Berghe, L.Vermeulen, P.Delerive, et al. A paradigm for gene regulation: inflammation, NF-kappaB and PPAR. Adv Exp Med Biol. 2003;544:181–196.
68. W.Kong, J.-H.Yen, E.Vassiliou, et al. Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis. 2010;9:12.
69. G.Zizzo, P.L.Cohen. The PPAR-γ antagonist GW9662 elicits differentiation of M2c-like cells and upregulation of the MerTK/Gas6 axis: a key role for PPAR-γ in human macrophage polarization. J Inflamm (Lond). 2015;12:36.
70. D.S.Im. Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages. Eur J Pharmacol. 2015, May 15 [Epub ahead of print] PMID: 25987421
71. A.Hirasawa, K.Tsumaya, T.Awaji, et al. Free fatty acids regulate gut incretin glucagon-like peptide- 1 secretion through GPR120. Nat. Med. 2005;11:90–94.
72. D.Y.Oh, S.Talukdar, E.J.Bae, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142:687–698.
73. K.Moore, Q.Zhang, N.Murgolo, et al Cloning, expression, and pharmacological characterization of the GPR120 free fatty acid receptor from cynomolgus monkey: comparison with human GPR120 splice variants. Comp Biochem Physiol B Biochem Mol Biol. 2009;154:419–426.
74. S.J.Watson, A.J.Brown, N.D.Holliday. Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol Pharmacol. 2012;81:631–642.
75. R.N.Burns, N.H.Moniri. Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem Biophys Res Commun. 2010;396:1030–1035.
76. O.B.Sánchez-Reyes, M.T.Romero-Ávila, J.A.Castillo-Badillo, et al. Free fatty acids and protein kinase C activation induce GPR120 (free fatty acid receptor 4) phosphorylation. Eur J Pharmacol. 2014;723:368–374.
77. L.M.Cornall, M.L.Mathai, D.H.Hryciw, et al. Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner. Cell Physiol Biochem. 2011;28:949–958.
78. A.Cheshmehkani, I.S.Senatorov, P.Kandi, et al. Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the rat colon. Inflamm Res. 2015;64:809–815.
79. Q.Wu, H.Wang, X.Zhao, et al. Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma. Oncogene. 2013;32:5541–5550.
80. W.Ying, A.Tseng, R.C.Chang, et al. MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation. J Clin Invest. 2015;125:4149–4159.
81. R.Jaenisch, A.Bird. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl.):S245–S254.
82. J.C.Chuang, P.A.Jones. Epigenetics and microRNAs. Pediatr Res. 2007;61:24R–29R.
83. N.Sadli, M.L.Ackland, D.De Mel, et al. Effects of zinc and DHA on the epigenetic regulation of human neuronal cells. Cell Physiol Biochem. 2012;29:87–98.
84. H.-S.Lee, A.Barraza-Villarreal, H.Hernandez-Vargas, et al. Modulation of DNA methylation states and infant immune system by dietary supplementation with ω-3 PUFA during pregnancy in an intervention study. Am J Clin Nutr. 2013;98:480–487.
85. M.Amarasekera, P.Noakes, D.Strickland, et al. Epigenome-wide analysis of neonatal CD4(+) T-cell DNA methylation sites potentially affected by maternal fish oil supplementation. Epigenetics. 2014;9:1570–1576.
86. M.Dimri, P.V.Bommi, A.A.Sahasrabuddhe, et al. Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis. 2010;31:489–495.
87. Y.Cho, N.D.Turner, L.A.Davidson, et al. A chemoprotective fish oil/pectin diet enhances apoptosis via Bcl-2 promoter methylation in rat azoxymethane-induced carcinomas. Exp Biol Med. 2012;237:1387–1393.
88. Y.Cho, N.D.Turner, L.A.Davidson, et al. Colon cancer cell apoptosis is induced by combined exposure to the ω-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med. 2014;239:302–310.•• The first study to show that DHA act as a regulator of the methylation state of apoptosis-related genes in colon.
89. S.A.Ross. Evidence for the relationship between diet and cancer. Exp Oncol. 2010;32:137–142.
90. P.Kachroo, I.Ivanov, L.A.Davidson, et al. Classification of diet-modulated gene signatures at the colon cancer initiation and progression stages. Dig Dis Sci. 2011;56:2595–2604.
91. J.P.Issa. DNA methylation as a therapeutic target in cancer. Clin Cancer Res. 2007;13:1634–1637.
92. G.Gopisetty, K.Ramachandran, R.Singal. DNA methylation and apoptosis. Mol Immunol. 2006;43:1729–1740.
93. B.Skender, A.H.Vaculova, J.Hofmanova. Docosahexaenoic fatty acid (DHA) in the regulation of colon cell growth and cell death: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012;156:186–199.
94. P.D.Biondo, D.N.Brindley, M.B.Sawyer, et al. The potential for treatment with dietary long-chain polyunsaturated ω-3 fatty acids during chemotherapy. J Nutr Biochem. 2008;19:787–796.
95. S.Serini, E.Piccioni, N.Merendino, et al. Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis. 2009;14:135–152.
96. S.S.Kolar, R.Barhoumi, E.S.Callaway, et al. Synergy between docosahexaenoic acid and butyrate elicits p53-independent apoptosis via mitochondrial Ca(2+) accumulation in colonocytes. Am J Physiol Gastrointest Liver Physiol. 2007;293:G935–43.
97. B.A.Narayanan, N.K.Narayanan, B.S.Reddy. Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int J Oncol. 2001;19:1255–1262.
98. G.Calviello, F.Di Nicuolo, S.Serini, et al. Docosahexaenoic acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil. Cancer Chemother Pharmacol. 2005;55:12–20.
99. N.Danbara, T.Yuri, M.Tsujita-Kyutoku, et al. Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells. Nutr Cancer. 2004;50:71–79.
100. K.Triff, E.Kim, R.S.Chapkin. Chemoprotective epigenetic mechanisms in a colorectal cancer model: modulation by ω-3 PUFA in combination with fermentable fiber. Curr Pharmacol Rep. 2015;1:11–20.
101. Z.Mahmood, Y.Shukla. Death receptors: targets for cancer therapy. Exp Cell Res. 2010;316:887–899.
102. S.-B.Jung, S.K.Kwon, M.Kwon, et al. Docosahexaenoic acid improves vascular function via up-regulation of SIRT1 expression in endothelial cells. Biochem Biophys Res Commun. 2013;437:114–119.
103. J.Ausio, F.Dong, K.E.van Holde. Use of selectively trypsinized nucleosome core particles to analyze the role of the histone “tails” in the stabilization of the nucleosome. J Mol Biol. 1989;206:451–463.
104. S.L.Berger. The complex language of chromatin regulation during transcription. Nature. 2007;447:407–412.
105. B.D.Strahl, R.Ohba, R.G.Cook, et al. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in tetrahymena. Proc Natl Acad Sci USA. 1999;96:14967–14972.
106. T.Kouzarides. Chromatin modifications and their function. Cell. 2007;128:693–705.
107. S.A.Ross, C.D.Davis. Microrna, nutrition, and cancer prevention. Adv Nutr. 2011;2:472–485.
108. M.I.Aslam, K.Taylor, J.H.Pringle, et al. MicroRNAs are novel biomarkers of colorectal cancer. Br J Surg. 2009;96:702–710.
109. O.Slaby, M.Svoboda, J.Michalek, et al. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009;8:102–115.
110. M.Nugent, N.Miller, M.J.Kerin. MicroRNAs in colorectal cancer: function, dysregulation and potential as novel biomarkers. Eur J Surg Oncol. 2011;37:649–654.
111. L.A.Davidson, N.Wang, M.S.Shah, et al. n-3 polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis. 2009;30:2077–2084.
112. M.S.Shah, S.L.Schwartz, C.Zhao, et al. Integrated microRNA and mRNA expression profiling in a rat colon carcinogenesis model: effect of a chemo-protective diet. Physiol Genomics. 2011;43:640–654.•• First study to investigate the possible modulating action of dietary ω-3 PUFA on microRNA in colon carcinogenesis.
113. L.Yao, C.Han, K.Song, et al. Omega-3 polyunsaturated fatty acids upregulate 15-PGDH expression in cholangiocarcinoma cells by inhibiting miR-26a/b expression. Cancer Res. 2015;75:1388–1398.
114. H.M.Hsiao, R.E.Sapinoro, T.H.Thatcher, et al. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS One. 2013;8:e58258.
115. C.Cipollina, S.Di Vincenzo, S.Gerbino, et al. Dual anti-oxidant and anti-inflammatory actions of the electrophilic cyclooxygenase-2-derived 17-oxo-DHA in lipopolysaccharide- and cigarette smoke-induced inflammation. Biochim Biophys Acta. 2014;1840:2299–2309.
116. A.L.Groeger, C.Cipollina, M.P.Cole, et al. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat Chem Biol. 2010;6:433–441.
117. J.Lefils-Lacourtablaise, M.Socorro, A.Géloën, et al. The eicosapentaenoic acid metabolite 15-deoxy-δ(12,14)-prostaglandin J3 increases adiponectin secretion by adipocytes partly via a PPARγ-dependent mechanism. PLoS One. 2013;8:e63997.
118. E.S.Musiek, J.D.Brooks, M.Joo, et al. Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J Biol Chem. 2008;283:19927–19935.
119. E.De Jong, P.Winkel, K.Poelstra, et al. Anticancer effects of 15d-prostaglandin-J2 in wild-type and doxorubicin-resistant ovarian cancer cells: novel actions on SIRT1 and HDAC. PLoS One. 2011;6:e25192.
120. K.Doyle, F.A.Fitzpatrick. Redox signaling, alkylation (carbonylation) of conserved cysteines inactivates class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function. J Biol Chem. 2010;285:17417–17424.
121. S.G.Codreanu, B.Zhang, S.M.Sobecki, et al. Global analysis of protein damage by the lipid electrophile 4-hydroxy-2-nonenal. Mol Cell Proteomics. 2009;8:670–680.
122. K.S.Fritz, J.J.Galligan, R.L.Smathers, et al. 4-hydroxynonenal inhibits SIRT3 via thiol-specific modification. Chem Res Toxicol. 2011;24:651–662.
123. K.C.Ravindra, V.Narayan, G.H.Lushington, et al. Targeting of histone acetyltransferase p300 by cyclopentenone prostaglandin Δ(12)-PGJ(2) through covalent binding to Cys(1438). Chem Res Toxicol. 2012;25:337–347.
124. S.Krishnamoorthy, A.Recchiuti, N.Chiang, et al. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am J Pathol. 2012;180:2018–2027.
125. D.J.Martino, S.L.Prescott. Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease. Allergy. 2010;65:7–15.
126. S.P.Hoile, N.A.Irvine, C.J.Kelsall, et al. Maternal fat intake in rats alters 20:4ω-6 and 22:6ω-3 status and the epigenetic regulation of Fads2 in offspring liver. J Nutr Biochem. 2013;24:1213–1220.
127. M.D.Niculescu, D.S.Lupu, C.N.Craciunescu. Perinatal manipulation of α-linolenic acid intake induces epigenetic changes in maternal and offspring livers. Faseb J. 2013;27:350–358.
128. D.L.Laskin, V.R.Sunil, C.R.Gardner, et al. Macrophages and tissue injury: agents of defense or destruction? Annu Rev Pharmacol Toxicol. 2011;51:267–288.
129. M.A.Bouhlel, B.Derudas, E.Rigamonti, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007;6:137–143.
130. X.Li, Y.Yu, C.D.Funk. Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). Faseb J. 2013;27:4987–4997.
131. Y.Liu, L.Y.Chen, M.Sokolowska, et al. The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A2 via GPR120 receptor to produce prostaglandin E2 and plays an anti-inflammatory role in macrophages. Immunology. 2014;143:81–95.
132. M.-C.Cathcart, J.Lysaght, G.P.Pidgeon. Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention. Cancer Metastasis Rev. 2011;30:363–385.
133. E.Titos, B.Rius, A.González-Périz, et al. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J Immunol. 2011;187:5408–5418.
134. J.Dalli, C.N.Serhan. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120:e60–72.
135. C.-Y.Chiu, B.Gomolka, C.Dierkes, et al. Omega-6 docosapentaenoic acid-derived resolvins and 17-hydroxydocosahexaenoic acid modulate macrophage function and alleviate experimental colitis. Inflamm Res. 2012;61:967–976.
136. R.Marcon, A.F.Bento, R.C.Dutra, et al. Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis. J Immunol. 2013;191:4288–4298.
137. S.Serini, G.Calviello. Reduction of oxidative/nitrosative stress in brain and its involvement in the neuroprotective effect of ω-3 PUFA in Alzheimer’s disease. Curr Alzheimer Res. 2015, Sep 20 [Epub ahead of print], PMID: 26391044.
138. S.C.Carvalho, L.M.Apolinário, S.M.Matheus, et al. EPA protects against muscle damage in the mdx mouse model of Duchenne muscular dystrophy by promoting a shift from the M1 to M2 macrophage phenotype. J Neuroimmunol. 2013;264:41–47.
139. D.A.Raptis, P.Limani, J.H.Jang, et al. GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids. J Hepatol. 2014;60:625–632.
140. A.A.De Boer, J.M.Monk, L.E.Robinson. Docosahexaenoic acid decreases pro-inflammatory mediators in an in vitro murine adipocyte macrophage co-culture model. PLoS One. 2014;9:e85037.
141. J.Clària, A.González-Périz, C.López-Vicario, et al. New insights into the role of macrophages in adipose tissue inflammation and fatty liver disease: modulation by endogenous omega-3 fatty acid-derived lipid mediators. Front Immunol. 2011;2:49.
142. C.N.Lumeng, S.M.Deyoung, J.L.Bodzin, et al. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007;56:16–23.
143. E.Oliver, F.C.McGillicuddy, K.A.Harford, et al. Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC ω-3 PUFA. J Nutr Biochem. 2012;23:1192–1200.
144. N.Satoh-Asahara, A.Shimatsu, Y.Sasaki, et al. Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia. Diabetes Care. 2012;35:2631–2639.
145. M.Spencer, B.S.Finlin, R.Unal, et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013;62:1709–1717.
146. B.S.Finlin, B.Zhu, C.P.Starnes, et al. Regulation of thrombospondin-1 expression in alternatively activated macrophages and adipocytes: role of cellular cross talk and omega-3 fatty acids. J Nutr Biochem. 2013;24:1571–1579.
147. J.M.Monk, T.Y.Hou, H.F.Turk, et al. Dietary ω-3 polyunsaturated fatty acids (PUFA) decrease obesity-associated Th17 cell-mediated inflammation during colitis. PLoS One. 2012;7:e49739.
148. J.Li, H.Jin, X.Wang. Epigenetic biomarkers: potential applications in gastrointestinal cancers. ISRN Gastroenterol. 2014;2014:464015.
149. W.Stillwell. The role of polyunsaturated lipids in membrane raft function. Scand J Food Nutr. 2006;50:107–113.
150. L.A.Michalowsky, P.A.Jones. Differential nuclear protein binding to 5-azacytosine-containing DNA as a potential mechanism for 5-aza-2’-deoxycytidine resistance. Mol Cell Biol. 1987;7:3076–3083.
151. L.Liu, R.C.Wylie, L.G.Andrews, et al. Aging, cancer and nutrition: the DNA methylation connection. Mech Ageing Dev. 2003;124:989–998.
152. C.M.Bender, M.M.Pao, P.A.Jones. Inhibition of DNA methylation by 5-aza-2’-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res. 1998;58:95–101.
153. R.Schneider-Stock, M.Diab-Assef, A.Rohrbeck, et al. 5-Aza-cytidine is a potent inhibitor of DNA methyltransferase 3 a and induces apoptosis in HCT-116 colon cancer cells via Gadd45- and p53-dependent mechanisms. J Pharmacol Exp Ther. 2005;312:525–536.
154. R.Humeniuk, P.J.Mishra, J.R.Bertino, et al. Epigenetic reversal of acquired resistance to 5-fluorouracil treatment. Mol Cancer Ther. 2009;8:1045–1054.
155. A.Link, F.Balaguer, Y.Shen, et al. Curcumin modulates DNA methylation in colorectal cancer cells. PLoS One. 2013;8:e57709.
156. Y.Gao, T.O.Tollefsbol. Impact of epigenetic dietary components on cancer through histone modifications. Curr Med Chem. 2015;22:2051–2064.