Folate pathways mediating the effects of ethanol in tumorigenesis

Boffetta, 2006, Alcohol and cancer, Lancet Oncol., 7, 149, 10.1016/S1470-2045(06)70577-0 Chen, 2014, Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis, Br. J. Canc., 110, 2327, 10.1038/bjc.2014.155 Kennedy, 2011, Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis, Cancer Epidemiol, 35, 2, 10.1016/j.canep.2010.11.004 Stevens, 2011, High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer, Gastroenterology, 141, 98, 10.1053/j.gastro.2011.04.004 Rossi, 2018, Colorectal cancer and alcohol consumption-populations to molecules, Cancers, 10, 10.3390/cancers10020038 Wien, 2012, Cancer risk with folic acid supplements: a systematic review and meta-analysis, BMJ Open, 2, 10.1136/bmjopen-2011-000653 Heinen, 2014, Dietary one-carbon nutrient intake and risk of lymphoid and myeloid neoplasms: results of The Netherlands cohort study, Canc. Epidemiol. Biomarkers Prev., 23, 2153, 10.1158/1055-9965.EPI-14-0136 Nishihara, 2014, Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region, Am. J. Clin. Nutr., 100, 1479, 10.3945/ajcn.114.095539 Mason, 2017, Folate status and colorectal cancer risk: a 2016 update, Mol. Aspect. Med., 53, 73, 10.1016/j.mam.2016.11.010 Jung, 2016, Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies, Int. J. Epidemiol., 45, 916, 10.1093/ije/dyv156 Zakhari, 2015, Alcohol and breast cancer: reconciling epidemiological and molecular data, Adv. Exp. Med. Biol., 815, 7, 10.1007/978-3-319-09614-8_2 Fagherazzi, 2015, Alcohol consumption and breast cancer risk subtypes in the E3N-EPIC cohort, Eur. J. Canc. Prev., 24, 209, 10.1097/CEJ.0000000000000031 Klarich, 2015, Moderate alcohol consumption and colorectal cancer risk, Alcohol Clin. Exp. Res., 39, 1280, 10.1111/acer.12778 Giacosa, 2013, Cancer prevention in Europe: the Mediterranean diet as a protective choice, Eur. J. Canc. Prev., 22, 90, 10.1097/CEJ.0b013e328354d2d7 Schwingshackl, 2014, Adherence to Mediterranean diet and risk of cancer: a systematic review and meta-analysis of observational studies, Int. J. Canc., 135, 1884, 10.1002/ijc.28824 Peng, 2016, Alcohol consumption and corresponding factors: a novel perspective on the risk factors of esophageal cancer, Oncol Lett, 11, 3231, 10.3892/ol.2016.4401 Galeone, 2015, Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium, Int. J. Canc., 136, 904, 10.1002/ijc.29044 Dumitrescu, 2005, The etiology of alcohol-induced breast cancer, Alcohol, 35, 213, 10.1016/j.alcohol.2005.04.005 Ratna, 2017, Alcohol and cancer: mechanisms and therapies, Biomolecules, 7, 10.3390/biom7030061 Strickland, 2013, Molecular mechanisms underlying the potentially adverse effects of folate, Clin. Chem. Lab. Med., 51, 607, 10.1515/cclm-2012-0561 Tibbetts, 2010, Compartmentalization of Mammalian folate-mediated one-carbon metabolism, Annu. Rev. Nutr., 30, 57, 10.1146/annurev.nutr.012809.104810 Fan, 2014, Quantitative flux analysis reveals folate-dependent NADPH production, Nature, 510, 298, 10.1038/nature13236 Ducker, 2017, One-carbon metabolism in health and disease, Cell Metabol., 25, 27, 10.1016/j.cmet.2016.08.009 Glynn, 1994, Folate and cancer: a review of the literature, Nutr. Canc., 22, 101, 10.1080/01635589409514336 Morscher, 2018, Mitochondrial translation requires folate-dependent tRNA methylation, Nature, 554, 128, 10.1038/nature25460 Kruman, 2002, Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease, J. Neurosci., 22, 1752, 10.1523/JNEUROSCI.22-05-01752.2002 Stover, 2004, Physiology of folate and vitamin B12 in health and disease, Nutr. Rev., 62, S3, 10.1111/j.1753-4887.2004.tb00070.x Stover, 2009, One-carbon metabolism-genome interactions in folate-associated pathologies, J. Nutr., 139, 2402, 10.3945/jn.109.113670 Tio, 2014, Folate intake and the risk of upper gastrointestinal cancers: a systematic review and meta-analysis, J. Gastroenterol. Hepatol., 29, 250, 10.1111/jgh.12446 Giovannucci, 2002, Epidemiologic studies of folate and colorectal neoplasia: a review, J. Nutr., 132, 2350S, 10.1093/jn/132.8.2350S Rodriguez, 2015, Folates induce colorectal carcinoma HT29 cell line proliferation through Notch1 signaling, Nutr. Canc., 67, 706, 10.1080/01635581.2015.1011285 Tomaszewski, 2011, Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate, Prostate, 71, 1287, 10.1002/pros.21346 Oleinik, 2014, Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation, J. Biol. Chem., 289, 26383, 10.1074/jbc.M114.569657 Ashkavand, 2017, Metabolic reprogramming by folate restriction leads to a less aggressive cancer phenotype, Mol. Canc. Res., 15, 189, 10.1158/1541-7786.MCR-16-0317 Chattopadhyay, 2007, Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications, Mol. Canc. Therapeut., 6, 404, 10.1158/1535-7163.MCT-06-0343 Goldman, 2010, The antifolates: evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs, Curr. Opin. Invest. Drugs, 11, 1409 Visentin, 2012, The antifolates, Hematol. Oncol. Clin. N. Am., 26, 629, 10.1016/j.hoc.2012.02.002 Longley, 2003, 5-fluorouracil: mechanisms of action and clinical strategies, Nat. Rev. Canc., 3, 330, 10.1038/nrc1074 Gonen, 2012, Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance, Drug Resist. Updates, 15, 183, 10.1016/j.drup.2012.07.002 Su, 2016, Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes, Oncotarget, 7, 33246, 10.18632/oncotarget.8910 Medici, 2013, Folate, alcohol, and liver disease, Mol. Nutr. Food Res., 57, 596, 10.1002/mnfr.201200077 Krupenko, 2018, ALDH1L1 and ALDH1L2 folate regulatory enzymes in cancer, Adv. Exp. Med. Biol., 1032, 127, 10.1007/978-3-319-98788-0_10 Zakhari, 2018, Epidemiology of moderate alcohol consumption and breast cancer: association or causation?, Cancers, 10, 10.3390/cancers10100349 Herbert, 1963, Correlation of folate deficiency with alcoholism and associated macrocytosis, anemia, and liver disease, Ann. Intern. Med., 58, 977, 10.7326/0003-4819-58-6-977 Sullivan, 1964, Suppression hematopoiesis by ethanol, J. Clin. Invest., 43, 2048, 10.1172/JCI105079 Hamid, 2007, Evaluation of the kinetic properties of the folate transport system in intestinal absorptive epithelium during experimental ethanol ingestion, Mol. Cell. Biochem., 304, 265, 10.1007/s11010-007-9509-3 Hamid, 2007, Down-regulation of reduced folate carrier may result in folate malabsorption across intestinal brush border membrane during experimental alcoholism, FEBS J., 274, 6317, 10.1111/j.1742-4658.2007.06150.x Moscow, 1995, Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells, Canc. Res., 55, 3790 Gelineau-van Waes, 2008, Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation, Birth Defects Res A Clin Mol Teratol, 82, 494, 10.1002/bdra.20453 Qiu, 2006, Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption, Cell, 127, 917, 10.1016/j.cell.2006.09.041 Piedrahita, 1999, Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development, Nat. Genet., 23, 228, 10.1038/13861 Visentin, 2014, The intestinal absorption of folates, Annu. Rev. Physiol., 76, 251, 10.1146/annurev-physiol-020911-153251 Hamid, 2009, New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development, FEBS J., 276, 2175, 10.1111/j.1742-4658.2009.06959.x Wani, 2012, Folate malabsorption is associated with down-regulation of folate transporter expression and function at colon basolateral membrane in rats, Br. J. Nutr., 107, 800, 10.1017/S0007114511003710 Said, 2010, Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption, Am. J. Physiol. Gastrointest. Liver Physiol., 298, G985, 10.1152/ajpgi.00068.2010 Wani, 2011, Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism, J. Cell. Physiol., 226, 579, 10.1002/jcp.22525 Wani, 2011, Biochemical and molecular mechanisms of folate transport in rat pancreas; interference with ethanol ingestion, PloS One, 6, 10.1371/journal.pone.0028599 Wani, 2012, Alcohol-associated folate disturbances result in altered methylation of folate-regulating genes, Mol. Cell. Biochem., 363, 157, 10.1007/s11010-011-1168-8 Farkas, 2015, DNA methylation and expression of the folate transporter genes in colorectal cancer, Tumour Biol, 36, 5581, 10.1007/s13277-015-3228-2 Wani, 2013, Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism, Alcohol, 47, 121, 10.1016/j.alcohol.2012.11.003 Hamid, 2007, Decreased expression of transporters reduces folate uptake across renal absorptive surfaces in experimental alcoholism, J. Membr. Biol., 220, 69, 10.1007/s00232-007-9075-3 Romanoff, 2007, Acute ethanol exposure inhibits renal folate transport, but repeated exposure upregulates folate transport proteins in rats and human cells, J. Nutr., 137, 1260, 10.1093/jn/137.5.1260 Matherly, 2018, The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer, Canc. Chemother. Pharmacol., 81, 1, 10.1007/s00280-017-3473-8 Cheung, 2016, Targeting folate receptor alpha for cancer treatment, Oncotarget, 7, 52553, 10.18632/oncotarget.9651 Cai, 2017, Expression status of folate receptor alpha is a predictor of survival in pancreatic ductal adenocarcinoma, Oncotarget, 8, 37646, 10.18632/oncotarget.16841 Suh, 2001, New perspectives on folate catabolism, Annu. Rev. Nutr., 21, 255, 10.1146/annurev.nutr.21.1.255 Caudill, 1998, Folate catabolism in pregnant and nonpregnant women with controlled folate intakes, J. Nutr., 128, 204, 10.1093/jn/128.2.204 Geoghegan, 1995, para-acetamidobenzoylglutamate is a suitable indicator of folate catabolism in rats, J. Nutr., 125, 2563 Higgins, 2000, The relationship between increased folate catabolism and the increased requirement for folate in pregnancy, BJOG, 107, 1149, 10.1111/j.1471-0528.2000.tb11115.x McNulty, 1995, Folate catabolism is related to growth rate in weanling rats, J. Nutr., 125, 99 Suh, 2000, Purification and properties of a folate-catabolizing enzyme, J. Biol. Chem., 275, 35646, 10.1074/jbc.M005864200 Kelly, 1981, Effect of acute and chronic alcohol ingestion on the rate of folate catabolism and hepatic enzyme induction in mice, Clin. Sci. (Lond.), 60, 221, 10.1042/cs0600221 Shaw, 1989, Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide, Biochem. J., 257, 277, 10.1042/bj2570277 Peter Guengerich, 2018, Roles of cytochrome P450 in metabolism of ethanol and carcinogens, Adv. Exp. Med. Biol., 1032, 15, 10.1007/978-3-319-98788-0_2 Heit, 2015, Transgenic mouse models for alcohol metabolism, toxicity, and cancer, Adv. Exp. Med. Biol., 815, 375, 10.1007/978-3-319-09614-8_22 Burgos-Barragan, 2017, Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism, Nature, 548, 549, 10.1038/nature23481 Pontel, 2015, Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen, Mol. Cell., 60, 177, 10.1016/j.molcel.2015.08.020 Hu, 2008, Disruption of circulation by ethanol promotes fetal alcohol spectrum disorder (FASD) in medaka (Oryzias latipes) embryogenesis, Comp. Biochem. Physiol. C Toxicol. Pharmacol., 148, 273, 10.1016/j.cbpc.2008.06.006 Krupenko, 2009, FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism, Chem. Biol. Interact., 178, 84, 10.1016/j.cbi.2008.09.007 Strickland, 2011, Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes, Chem. Biol. Interact., 191, 122, 10.1016/j.cbi.2010.12.025 Zheng, 2018, Mitochondrial one-carbon pathway supports cytosolic folate integrity in cancer cells, Cell, 175, 1546, 10.1016/j.cell.2018.09.041 Chang, 2014, Knocking down 10-Formyltetrahydrofolate dehydrogenase increased oxidative stress and impeded zebrafish embryogenesis by obstructing morphogenetic movement, Biochim. Biophys. Acta, 1840, 2340, 10.1016/j.bbagen.2014.04.009 Hsiao, 2014, Ethanol-induced upregulation of 10-formyltetrahydrofolate dehydrogenase helps relieve ethanol-induced oxidative stress, Mol. Cell Biol., 34, 498, 10.1128/MCB.01427-13 Krupenko, 2019, Loss of ALDH1L1 folate enzyme confers a selective metabolic advantage for tumor progression, Chem. Biol. Interact., 302, 149, 10.1016/j.cbi.2019.02.013 Jain, 2012, Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation, Science, 336, 1040, 10.1126/science.1218595 Gupta, 2017, Serine hydroxymethyl transferase 1 stimulates pro-oncogenic cytokine expression through sialic acid to promote ovarian cancer tumor growth and progression, Oncogene, 36, 4014, 10.1038/onc.2017.37 Villanueva, 2004, Hepatic transmethylation reactions in micropigs with alcoholic liver disease, Hepatology, 39, 1303, 10.1002/hep.20168 Varela-Rey, 2013, Alcohol, DNA methylation, and cancer, Alcohol Res, 35, 25 Yoshida, 1997, Ethanol represses thymidylate synthase and thymidine kinase at mRNA level in regenerating rat liver after partial hepatectomy, Biochim. Biophys. Acta, 1336, 180, 10.1016/S0304-4165(97)00025-1 Feltes, 2014, Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis, OMICS, 18, 344, 10.1089/omi.2013.0144 Bailey, 2009, The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake, Proc. Natl. Acad. Sci. U. S. A., 106, 15424, 10.1073/pnas.0902072106 Bertino, 2009, Cancer research: from folate antagonism to molecular targets, Best Pract. Res. Clin. Haematol., 22, 577, 10.1016/j.beha.2009.09.004 Raz, 2016, Folylpoly-gamma-glutamate synthetase: a key determinant of folate homeostasis and antifolate resistance in cancer, Drug Resist. Updates, 28, 43, 10.1016/j.drup.2016.06.004 Suzuki, 2008, Alcohol drinking and one-carbon metabolism-related gene polymorphisms on pancreatic cancer risk, Canc. Epidemiol. Biomarkers Prev., 17, 2742, 10.1158/1055-9965.EPI-08-0470 Sangrajrang, 2010, Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women, Breast Canc. Res. Treat., 123, 885, 10.1007/s10549-010-0804-4 Svensson, 2016, Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study, Sci. Rep., 6, 36607, 10.1038/srep36607 Cheng, 2015, Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: women's Health Initiative Observational Study, Cancer, 121, 3684, 10.1002/cncr.29465 Suzuki, 2007, One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study, Canc. Sci., 98, 1439, 10.1111/j.1349-7006.2007.00533.x Suzuki, 2007, Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study, Carcinogenesis, 28, 1718, 10.1093/carcin/bgm104 Frosst, 1995, A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase, Nat. Genet., 10, 111, 10.1038/ng0595-111 Fowler, 2012, Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain, J. Biol. Chem., 287, 43533, 10.1074/jbc.M112.401497 Saffroy, 2008, Protective effect against alcohol dependence of the thermolabile variant of MTHFR, Drug Alcohol Depend., 96, 30, 10.1016/j.drugalcdep.2008.01.016 Halsted, 2002, Interactions of ethanol and folate deficiency in development of alcoholic liver disease in the micropig, Trans. Am. Clin. Climatol. Assoc., 113, 151 Halsted, 2002, Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig, Proc. Natl. Acad. Sci. U. S. A., 99, 10072, 10.1073/pnas.112336399 Blom, 2006, Neural tube defects and folate: case far from closed, Nat. Rev. Neurosci., 7, 724, 10.1038/nrn1986 Hoyme, 2016, Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders, Pediatrics, 138, 10.1542/peds.2015-4256 Cook, 2016, N. Canada Fetal Alcohol Spectrum Disorder Research, Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan, CMAJ (Can. Med. Assoc. J.), 188, 191, 10.1503/cmaj.141593 Riley, 2011, Fetal alcohol spectrum disorders: an overview, Neuropsychol. Rev., 21, 73, 10.1007/s11065-011-9166-x Ma, 2010, The relationship between early embryo development and tumourigenesis, J. Cell Mol. Med., 14, 2697, 10.1111/j.1582-4934.2010.01191.x Guo, 2009, Signaling cross-talk between TGF-beta/BMP and other pathways, Cell Res., 19, 71, 10.1038/cr.2008.302 Maguire, 2015, Tumors of the neural crest: common themes in development and cancer, Dev. Dynam., 244, 311, 10.1002/dvdy.24226 Hadjimichael, 2015, Common stemness regulators of embryonic and cancer stem cells, World J. Stem Cell., 7, 1150, 10.4252/wjsc.v7.i9.1150 Mead, 2014, Fetal alcohol spectrum disorders and their transmission through genetic and epigenetic mechanisms, Front. Genet., 5, 154, 10.3389/fgene.2014.00154 Flentke, 2019, Alcohol-mediated calcium signals dysregulate pro-survival Snai2/PUMA/Bcl2 networks to promote p53-mediated apoptosis in avian neural crest progenitors, Birth Defects Res, 111, 686, 10.1002/bdr2.1508 Hoeferlin, 2011, Activation of p21-dependent G1/G2 arrest in the absence of DNA damage as an antiapoptotic response to metabolic stress, Genes Cancer, 2, 889, 10.1177/1947601911432495 Hoeferlin, 2013, Folate stress induces apoptosis via p53-dependent de novo ceramide synthesis and up-regulation of ceramide synthase 6, J. Biol. Chem., 288, 12880, 10.1074/jbc.M113.461798 Fekry, 2018, C16-ceramide is a natural regulatory ligand of p53 in cellular stress response, Nat. Commun., 9, 4149, 10.1038/s41467-018-06650-y Robertson, 2000, DNA methylation in health and disease, Nat. Rev. Genet., 1, 11, 10.1038/35049533 Smith, 2013, DNA methylation: roles in mammalian development, Nat. Rev. Genet., 14, 204, 10.1038/nrg3354 Okano, 1999, DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development, Cell, 99, 247, 10.1016/S0092-8674(00)81656-6 Baylin, 2000, DNA hypermethylation in tumorigenesis: epigenetics joins genetics, Trends Genet., 16, 168, 10.1016/S0168-9525(99)01971-X Baylin, 2011, A decade of exploring the cancer epigenome - biological and translational implications, Nat. Rev. Canc., 11, 726, 10.1038/nrc3130 Jones, 2007, The epigenomics of cancer, Cell, 128, 683, 10.1016/j.cell.2007.01.029 Berres, 2017, Transcriptome profiling identifies ribosome biogenesis as a target of alcohol teratogenicity and vulnerability during early embryogenesis, PloS One, 12, 10.1371/journal.pone.0169351 Masuo, 2009, Omic analyses unravels global molecular changes in the brain and liver of a rat model for chronic Sake (Japanese alcoholic beverage) intake, Electrophoresis, 30, 1259, 10.1002/elps.200900045 Zeng, 2017, Proteomics and metabolomics analysis of hepatic mitochondrial metabolism in alcohol-preferring and non-preferring rats, Oncotarget, 8, 102020, 10.18632/oncotarget.22040 Al-Shaer, 2019, Exon level machine learning analyses elucidate novel candidate miRNA targets in an avian model of fetal alcohol spectrum disorder, PLoS Comput. Biol., 15, 10.1371/journal.pcbi.1006937 Yin, 2009, Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice, Toxicol. Appl. Pharmacol., 235, 312, 10.1016/j.taap.2008.12.018 Narla, 2010, Ribosomopathies: human disorders of ribosome dysfunction, Blood, 115, 3196, 10.1182/blood-2009-10-178129 Ajore, 2017, Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations, EMBO Mol. Med., 9, 498, 10.15252/emmm.201606660 Koufaris, 2018, Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation, Canc. Metabol., 6, 12, 10.1186/s40170-018-0185-4 Gustafsson Sheppard, 2015, The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation, Sci. Rep., 5, 15029, 10.1038/srep15029 Nilsson, 2014, Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer, Nat. Commun., 5, 3128, 10.1038/ncomms4128 Ben-Sahra, 2016, mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle, Science, 351, 728, 10.1126/science.aad0489 Miyo, 2017, The importance of mitochondrial folate enzymes in human colorectal cancer, Oncol. Rep., 37, 417, 10.3892/or.2016.5264 Pikman, 2016, Targeting MTHFD2 in acute myeloid leukemia, J. Exp. Med., 213, 1285, 10.1084/jem.20151574 Tedeschi, 2015, Mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) overexpression is associated with tumor cell proliferation and is a novel target for drug development, Mol. Canc. Res., 13, 1361, 10.1158/1541-7786.MCR-15-0117 Green, 2019, MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma, Oncogene, 38, 6211, 10.1038/s41388-019-0869-4 Balaraman, 2013, Dysregulation of microRNA expression and function contributes to the etiology of fetal alcohol spectrum disorders, Alcohol Res, 35, 18 Torres, 2018, Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease, World J. Gastroenterol., 24, 4104, 10.3748/wjg.v24.i36.4104 Mandal, 2018, Maternal alcohol consumption and altered miRNAs in the developing fetus: context and future perspectives, J. Appl. Toxicol., 38, 100, 10.1002/jat.3504 Nagadia, 2013, miRNAs in head and neck cancer revisited, Cell. Oncol., 36, 1, 10.1007/s13402-012-0122-4 Farazi, 2011, miRNAs in human cancer, J. Pathol., 223, 102, 10.1002/path.2806 Iorio, 2012, MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review, EMBO Mol. Med., 4, 143, 10.1002/emmm.201100209 Calin, 2006, MicroRNA signatures in human cancers, Nat. Rev. Canc., 6, 857, 10.1038/nrc1997 Shah, 2012, Mechanistic insights into the role of microRNAs in cancer: influence of nutrient crosstalk, Front. Genet., 3, 305, 10.3389/fgene.2012.00305 Beckett, 2017, Folate and microRNA: bidirectional interactions, Clin. Chim. Acta, 474, 60, 10.1016/j.cca.2017.09.001 Shookhoff, 2010, A new perspective on neural tube defects: folic acid and microRNA misexpression, Genesis, 48, 282 Marsit, 2006, MicroRNA responses to cellular stress, Canc. Res., 66, 10843, 10.1158/0008-5472.CAN-06-1894 Kutay, 2006, Downregulation of miR-122 in the rodent and human hepatocellular carcinomas, J. Cell. Biochem., 99, 671, 10.1002/jcb.20982 Satishchandran, 2018, MicroRNA 122, regulated by GRLH2, protects livers of mice and patients from ethanol-induced liver disease, Gastroenterology, 154, 238, 10.1053/j.gastro.2017.09.022 Beckett, 2015, Folate status, folate-related genes and serum miR-21 expression: implications for miR-21 as a biomarker, BBA Clin, 4, 45, 10.1016/j.bbacli.2015.06.006 Shah, 2017, Combination of vitamin B12 active forms improved fetal growth in Wistar rats through up-regulation of placental miR-16 and miR-21 levels, Life Sci., 191, 97, 10.1016/j.lfs.2017.10.017 Sathyan, 2007, Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium, J. Neurosci., 27, 8546, 10.1523/JNEUROSCI.1269-07.2007 Dippold, 2012, Chronic ethanol feeding enhances miR-21 induction during liver regeneration while inhibiting proliferation in rats, Am. J. Physiol. Gastrointest. Liver Physiol., 303, G733, 10.1152/ajpgi.00019.2012 Marts, 2017, MiR-21-Mediated suppression of Smad7 induces TGFbeta1 and can Be inhibited by activation of Nrf2 in alcohol-treated lung fibroblasts, Alcohol Clin. Exp. Res., 41, 1875, 10.1111/acer.13496 Baker, 2017, Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status, Mol. Nutr. Food Res., 61, 10.1002/mnfr.201600646 Ignacio, 2014, Effects of acute prenatal exposure to ethanol on microRNA expression are ameliorated by social enrichment, Front Pediatr, 2, 103, 10.3389/fped.2014.00103 Li, 2019, Maternal folic acid deficiency stimulates neural cell apoptosis via miR-34a associated with Bcl-2 in the rat foetal brain, Int. J. Dev. Neurosci., 72, 6, 10.1016/j.ijdevneu.2018.11.002 Geoffroy, 2017, Late maternal folate supplementation rescues from methyl donor deficiency-associated brain defects by restoring let-7 and miR-34 pathways, Mol. Neurobiol., 54, 5017, 10.1007/s12035-016-0035-8 Meng, 2012, Epigenetic regulation of miR-34a expression in alcoholic liver injury, Am. J. Pathol., 181, 804, 10.1016/j.ajpath.2012.06.010 Hermeking, 2010, The miR-34 family in cancer and apoptosis, Cell Death Differ., 17, 193, 10.1038/cdd.2009.56 Krichevsky, 2009, miR-21: a small multi-faceted RNA, J. Cell Mol. Med., 13, 39, 10.1111/j.1582-4934.2008.00556.x le Sage, 2007, Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation, EMBO J., 26, 3699, 10.1038/sj.emboj.7601790 Wang, 2009, Ethanol exposure induces differential microRNA and target gene expression and teratogenic effects which can be suppressed by folic acid supplementation, Hum. Reprod., 24, 562, 10.1093/humrep/den439 Lund, 2010, miR-10 in development and cancer, Cell Death Differ., 17, 209, 10.1038/cdd.2009.58 Bi, 2018, MicroRNA-10a/b are regulators of myeloid differentiation and acute myeloid leukemia, Oncol Lett, 15, 5611 Balatti, 2019, MicroRNA profiling of salivary duct carcinoma versus her2/neu overexpressing breast carcinoma identify miR-10a as a putative breast related oncogene, Head Neck Pathol, 13, 344, 10.1007/s12105-018-0971-x Bourguignon, 2010, Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion, J. Biol. Chem., 285, 36721, 10.1074/jbc.M110.162305 Bourguignon, 2016, Up-regulation of histone methyltransferase, DOT1L, by matrix hyaluronan promotes MicroRNA-10 expression leading to tumor cell invasion and chemoresistance in cancer stem cells from head and neck squamous cell carcinoma, J. Biol. Chem., 291, 10571, 10.1074/jbc.M115.700021 Oleinik, 2010, ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A, Oncogene, 29, 6233, 10.1038/onc.2010.356 Stanger, 2012, Enzymatic and non-enzymatic antioxidative effects of folic acid and its reduced derivates, Subcell. Biochem., 56, 131, 10.1007/978-94-007-2199-9_8 Lai, 2017, Novel roles of folic acid as redox regulator: modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma, Tumour Biol, 39, 10.1177/1010428317702649 Albano, 2006, Alcohol, oxidative stress and free radical damage, Proc. Nutr. Soc., 65, 278, 10.1079/PNS2006496 Das, 2007, Alcohol-induced oxidative stress, Life Sci., 81, 177, 10.1016/j.lfs.2007.05.005 Zakhari, 2013, Alcohol metabolism and epigenetics changes, Alcohol Res, 35, 6 Ojeda, 2018, The role of folic acid and selenium against oxidative damage from ethanol in early life programming: a review, Biochem. Cell. Biol., 96, 178, 10.1139/bcb-2017-0069 Arteel, 2003, Oxidants and antioxidants in alcohol-induced liver disease, Gastroenterology, 124, 778, 10.1053/gast.2003.50087 Zhang, 2018, A review of interventions against fetal alcohol spectrum disorder targeting oxidative stress, Int. J. Dev. Neurosci., 71, 140, 10.1016/j.ijdevneu.2018.09.001 Cano, 2001, Protective effect of folic acid against oxidative stress produced in 21-day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period, Free Radic. Res., 34, 1, 10.1080/10715760100300011 Milne, 2012, Maternal use of folic acid and other supplements and risk of childhood brain tumors, Canc. Epidemiol. Biomarkers Prev., 21, 1933, 10.1158/1055-9965.EPI-12-0803 Chiavarini, 2018, Maternal folate intake and risk of childhood brain and spinal cord tumors: a systematic review and meta-analysis, Neuroepidemiology, 51, 82, 10.1159/000490249 Ly, 2011, Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring, Canc. Res., 71, 988, 10.1158/0008-5472.CAN-10-2379 Sie, 2011, Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring, Gut, 60, 1687, 10.1136/gut.2011.238782 Thompson, 2001, Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study, Lancet, 358, 1935, 10.1016/S0140-6736(01)06959-8 Ciappio, 2011, Maternal one-carbon nutrient intake and cancer risk in offspring, Nutr. Rev., 69, 561, 10.1111/j.1753-4887.2011.00424.x Joshi, 2001, Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity, Free Radic. Biol. Med., 30, 1390, 10.1016/S0891-5849(01)00543-3 Obeid, 2006, Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia, FEBS Lett., 580, 2994, 10.1016/j.febslet.2006.04.088 Mattson, 2003, Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders, Trends Neurosci., 26, 137, 10.1016/S0166-2236(03)00032-8 Hwang, 2011, Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney, Am. J. Physiol. Ren. Physiol., 300, F189, 10.1152/ajprenal.00272.2010 Nath, 2012, Hypoxia and hypoxia inducible factors: diverse roles in liver diseases, Hepatology, 55, 622, 10.1002/hep.25497 French, 2004, The role of hypoxia in the pathogenesis of alcoholic liver disease, Hepatol. Res., 29, 69, 10.1016/j.hepres.2004.02.006 Guzy, 2005, Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metabol., 1, 401, 10.1016/j.cmet.2005.05.001 Cheng, 2016, Folic acid attenuates vascular endothelial cell injury caused by hypoxia via the inhibition of ERK1/2/NOX4/ROS pathway, Cell Biochem. Biophys., 74, 205, 10.1007/s12013-016-0723-z Moens, 2008, Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease, Am. J. Physiol. Heart Circ. Physiol., 294, H1971, 10.1152/ajpheart.91503.2007 Gao, 2009, Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity, J. Mol. Cell. Cardiol., 47, 752, 10.1016/j.yjmcc.2009.07.025 Chalupsky, 2015, Folic acid promotes recycling of tetrahydrobiopterin and protects against hypoxia-induced pulmonary hypertension by recoupling endothelial nitric oxide synthase, Antioxidants Redox Signal., 23, 1076, 10.1089/ars.2015.6329 Gielis, 2011, Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders, Free Radic. Biol. Med., 50, 765, 10.1016/j.freeradbiomed.2010.12.018 Harris, 2002, Hypoxia--a key regulatory factor in tumour growth, Nat. Rev. Canc., 2, 38, 10.1038/nrc704 Wilson, 2011, Targeting hypoxia in cancer therapy, Nat. Rev. Canc., 11, 393, 10.1038/nrc3064 Semenza, 2012, Hypoxia-inducible factors in physiology and medicine, Cell, 148, 399, 10.1016/j.cell.2012.01.021 Semenza, 2017, Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype, EMBO J., 36, 252, 10.15252/embj.201695204 Gorrini, 2013, Modulation of oxidative stress as an anticancer strategy, Nat. Rev. Drug Discov., 12, 931, 10.1038/nrd4002 Raz, 2014, Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest, Cell Death Dis., 5, 10.1038/cddis.2014.39 Ju, 2019, Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: mechanisms and therapeutic implications, J. Natl. Cancer Inst., 111, 584, 10.1093/jnci/djy160 Ma, 2018, Folic acid supplementation repressed hypoxia-induced inflammatory response via ROS and JAK2/STAT3 pathway in human promyelomonocytic cells, Nutr. Res., 53, 40, 10.1016/j.nutres.2018.03.007 Meadows, 2015, Effects of alcohol on tumor growth, metastasis, immune response, and host survival, Alcohol Res, 37, 311 Zhang, 2015, Alcohol consumption and antitumor immunity: dynamic changes from activation to accelerated deterioration of the immune system, Adv. Exp. Med. Biol., 815, 313, 10.1007/978-3-319-09614-8_18 Mason, 2011, Unraveling the complex relationship between folate and cancer risk, Biofactors, 37, 253, 10.1002/biof.174