{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:26:53Z","timestamp":1775035613142,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,7,29]],"date-time":"2017-07-29T00:00:00Z","timestamp":1501286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Cigarette smoke (CS) causes about 480,000 deaths each year worldwide, and it is well-known to have harmful effects on the human body, leading to heart disease, stroke, lung cancer, and cardiovascular problems. In this study, the effects of formaldehyde (FA) and benzene (Bz), the main components of CS, on cell proliferation and epithelial mesenchymal transition (EMT) of JEG-3 human choriocarcinoma cells were examined to confirm the relationship between CS components and placenta carcinoma. Upon MTT assay, FA (10\u22128 M to 10\u22125 M) and Bz (10\u221211 M to 10\u22128 M) increased JEG-3 cell proliferation. Western blot assay revealed that the protein expression of cyclin D1 and E1 increased, while the levels of p21 and p27 were reduced following treatment. In Scratch assay, FA (10\u22128 M and 10\u22125 M) and Bz (10\u221211 M and 10\u22128 M) increased migration of JEG-3 cells at 24 h and 48 h compared with that at 0 h. In addition, the expression of the epithelial marker, E-cadherin, was significantly decreased, while the expression of the mesenchymal marker, N-cadherin, was significantly increased by FA (10\u22128 M and 10\u22125 M) and Bz (10\u221211 M and 10\u22128 M). snail and slug transcriptional factors were associated with EMT, which were also up-regulated by FA and Bz, indicating that FA and Bz lead to an increase in the EMT process in JEG-3 choriocarcinoma cells. We further evaluated reactive oxygen species (ROS) and activation of antioxidant effect using dichlorofluorescin diacetate (DCFH-DA) and Western blot assay. FA and Bz increased the ROS production and an antioxidant related marker, Nrf2, in JEG-3 cells. However, eIF2\u03b1 levels were reduced by FA and Bz via activation of the antioxidant reaction. Taken together, these results indicated that FA and Bz induce the growth and migration of human choriocarcinoma cells via regulation of the cell cycle and EMT and activation of ROS and antioxidant related markers.<\/jats:p>","DOI":"10.3390\/ijerph14080854","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T03:30:06Z","timestamp":1501558206000},"page":"854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Treatment of Human Placental Choriocarcinoma Cells with Formaldehyde and Benzene Induced Growth and Epithelial Mesenchymal Transition via Induction of an Antioxidant Effect"],"prefix":"10.3390","volume":"14","author":[{"given":"Hae-Miru","family":"Lee","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo-Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1925-1198","authenticated-orcid":false,"given":"Kyung-Chul","family":"Choi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1002\/cncr.28904","article-title":"The biologic effects of cigarette smoke on cancer cells","volume":"120","author":"Sobus","year":"2014","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0025-7125(16)30355-8","article-title":"The health consequences of smoking: Cancer","volume":"76","author":"Newcomb","year":"1992","journal-title":"Med. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/j.bbagen.2016.07.008","article-title":"Nicotine enhances the malignant potential of human pancreatic cancer cells via activation of atypical protein kinase C","volume":"1860","author":"Hanaki","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/tox.22271","article-title":"Cigarette smoke extracts induced the colon cancer migration via regulating epithelial mesenchymal transition and metastatic genes in human colon cancer cells","volume":"32","author":"Kim","year":"2016","journal-title":"Environ. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/ijc.27339","article-title":"Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies","volume":"131","author":"Pesch","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2471\/BLT.10.079905","article-title":"Gender empowerment and female-to-male smoking prevalence ratios","volume":"89","author":"Hitchman","year":"2011","journal-title":"Bull. World Health Organ."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"275","DOI":"10.5487\/TR.2016.32.4.275","article-title":"Maternal Nicotine Exposure During Late Gestation and Lactation Increases Anxiety-Like and Impulsive Decision-Making Behavior in Adolescent Offspring of Rat","volume":"32","author":"Lee","year":"2016","journal-title":"Toxicol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.yrtph.2015.01.006","article-title":"Variation in tobacco and mainstream smoke toxicant yields from selected commercial cigarette products","volume":"71","author":"Eldridge","year":"2015","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1093\/carcin\/8.5.729","article-title":"Toxic and carcinogenic agents in undiluted mainstream smoke and sidestream smoke of different types of cigarettes","volume":"8","author":"Adams","year":"1987","journal-title":"Carcinogenesis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/BF01637079","article-title":"Significance of exposure to benzene and other toxic compounds through environmental tobacco smoke","volume":"116","author":"Adlkofer","year":"1990","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_11","unstructured":"World Health Organization (2000). Air Quality Guidelines for Europe, WHO."},{"key":"ref_12","unstructured":"World Health Organization (2010). WHO Guidelines for Indoor Air Quality: Selected Pollutants, WHO."},{"key":"ref_13","first-page":"277","article-title":"Physiological and psychological effects of passive smoking (author\u2019s transl)","volume":"37","author":"Fischer","year":"1976","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1172\/JCI200422991","article-title":"Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface","volume":"114","author":"Zhou","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hod, T., Cerdeira, A.S., and Karumanchi, S.A. (2015). Molecular Mechanisms of Preeclampsia. Cold Spring Harb. Perspect. Med., 5.","DOI":"10.1101\/cshperspect.a023473"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lee, G.A., Hwang, K.A., and Choi, K.C. (2016). Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis. Toxins, 8.","DOI":"10.3390\/toxins8060162"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nrc1075","article-title":"Tumour-cell invasion and migration: Diversity and escape mechanisms","volume":"3","author":"Friedl","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.reprotox.2016.06.012","article-title":"Effects of cigarette smoke extracts on the progression and metastasis of human ovarian cancer cells via regulating epithelial-mesenchymal transition","volume":"65","author":"Jeon","year":"2016","journal-title":"Reprod. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"59199","DOI":"10.18632\/oncotarget.10498","article-title":"Role of a7-nicotinic acetylcholine receptor in nicotine-induced invasion and epithelial-to-mesenchymal transition in human non-small cell lung cancer cells","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1083\/jcb.201102095","article-title":"Signal transduction by reactive oxygen species","volume":"194","author":"Finkel","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.pharmthera.2009.11.004","article-title":"Transcriptional responses to oxidative stress: Pathological and toxicological implications","volume":"125","author":"Ma","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"ref_23","first-page":"62","article-title":"RTP801 Amplifies Nox-4-dependent Oxidative Stress Induced by Cigarette Smoke","volume":"56","author":"Sanders","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2021","DOI":"10.1038\/cddis.2015.364","article-title":"Cigarette toxicity triggers Leber\u2019s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways","volume":"6","author":"Giordano","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"390","DOI":"10.7555\/JBR.28.20120118","article-title":"Acute effect of aspartame-induced oxidative stress in Wistar albino rat brain","volume":"29","author":"Ashok","year":"2015","journal-title":"J. Biomed. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3718","DOI":"10.1111\/febs.13755","article-title":"Long and short (timeframe) of endoplasmic reticulum stress-induced cell death","volume":"283","author":"Ryoo","year":"2016","journal-title":"FEBS J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bcp.2016.04.008","article-title":"The endoplasmic reticulum stress\/unfolded protein response in gliomagenesis, tumor progression and as a therapeutic target in glioblastoma","volume":"118","author":"Meijer","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"203","DOI":"10.7555\/JBR.30.2016K0012","article-title":"Effect of vitamin D3 on production of progesterone in porcine granulosa cells by regulation of steroidogenic enzymes","volume":"30","author":"Hong","year":"2016","journal-title":"J. Biomed. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.biocel.2005.09.018","article-title":"Coordination of ER and oxidative stress signaling: The PERK\/Nrf2 signaling pathway","volume":"38","author":"Cullinan","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12975-012-0245-y","article-title":"Nrf2 to pre-condition the brain against injury caused by products of hemolysis after ICH","volume":"4","author":"Zhao","year":"2013","journal-title":"Transl. Stroke Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7198","DOI":"10.1128\/MCB.23.20.7198-7209.2003","article-title":"Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival","volume":"23","author":"Cullinan","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/j.etap.2014.04.013","article-title":"Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway","volume":"37","author":"Kim","year":"2014","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s10549-014-2927-5","article-title":"Epithelial mesenchymal transition in early invasive breast cancer: An immunohistochemical and reverse phase protein array study","volume":"145","author":"Aleskandarany","year":"2014","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/S0890-6238(00)00107-6","article-title":"Concordant in situ and in vitro data show that maternal cigarette smoking negatively regulates placental cytotrophoblast passage through the cell cycle","volume":"14","author":"Genbacev","year":"2000","journal-title":"Reprod. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0890-6238(03)00094-7","article-title":"Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy","volume":"17","author":"Genbacev","year":"2003","journal-title":"Reprod. Toxicol."},{"key":"ref_36","first-page":"5","article-title":"Nicotine and gastrointestinal disorders: Its role in ulceration and cancer development","volume":"19","author":"Chu","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_37","first-page":"551","article-title":"Cigarette smoking during pregnancy: Acute effects on uterine flow velocity waveforms","volume":"81","author":"Castro","year":"1993","journal-title":"Obstet. Gynecol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.fertnstert.2008.09.074","article-title":"Cigarette smoke inhibits endometrial epithelial cell proliferation through a nitric oxide-mediated pathway","volume":"93","author":"Khorram","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1679\/aohc.67.465","article-title":"Expression of the arylhydrocarbon receptor in the peri-implantation period of the mouse uterus and the impact of dioxin on mouse implantation","volume":"67","author":"Kitajima","year":"2004","journal-title":"Arch. Histol. Cytol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/366704a0","article-title":"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\/CDK4","volume":"366","author":"Serrano","year":"1993","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1126\/science.1388288","article-title":"Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle","volume":"257","author":"Koff","year":"1992","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/366701a0","article-title":"P21 is a universal inhibitor of cyclin kinases","volume":"366","author":"Xiong","year":"1993","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1126\/science.7624798","article-title":"Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27","volume":"269","author":"Pagano","year":"1995","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40169-015-0048-3","article-title":"EMT and tumor metastasis","volume":"4","author":"Heerboth","year":"2015","journal-title":"Clin. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1177\/147323000903700531","article-title":"The wound healing process: An overview of the cellular and molecular mechanisms","volume":"37","author":"Velnar","year":"2009","journal-title":"J. Int. Med. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1083\/jcb.137.6.1403","article-title":"The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition","volume":"137","author":"Savagner","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.etap.2016.05.016","article-title":"Three components of cigarette smoke altered the growth and apoptosis of metastatic colon cancer cells via inducing the synthesis of reactive oxygen species and endoplasmic reticulum stress","volume":"45","author":"Lee","year":"2016","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cbi.2016.01.005","article-title":"ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells","volume":"245","author":"Gu","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.3892\/mmr.2015.3490","article-title":"Acetyl-l-carnitine prevents homocysteine-induced suppression of Nrf2\/Keap1 mediated antioxidation in human lens epithelial cells","volume":"12","author":"Yang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.stem.2014.05.009","article-title":"Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling","volume":"15","author":"Paul","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1158\/1535-7163.MCT-16-0271","article-title":"Alkylating agent induced NRF2 blocks endoplasmic reticulum stress-mediated apoptosis via control of glutathione pools and protein thiol homeostasis","volume":"15","author":"Masamsetti","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1007\/s00125-016-4040-2","article-title":"Placental endoplasmic reticulum stress in gestational diabetes: The potential for therapeutic intervention with chemical chaperones and antioxidants","volume":"59","author":"Yung","year":"2016","journal-title":"Diabetologia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.freeradbiomed.2013.06.041","article-title":"Oncogenic functions of the transcription factor Nrf2","volume":"65","author":"Wei","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/dote.12124","article-title":"Blockage of Nrf2 suppresses the migration and invasion of esophageal squamous cell carcinoma cells in hypoxic microenvironment","volume":"27","author":"Shen","year":"2014","journal-title":"Dis. Esophagus"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1016\/j.jss.2010.05.058","article-title":"Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival","volume":"164","author":"Wang","year":"2010","journal-title":"J. Surg. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"73593","DOI":"10.18632\/oncotarget.12435","article-title":"NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA\/ROCK pathway signal transduction","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbagen.2016.10.006","article-title":"Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3\/Nrf2 pathway in pancreatic cancer cells","volume":"1861","author":"Wu","year":"2017","journal-title":"Biochim. Biophys. Acta"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/14\/8\/854\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:30Z","timestamp":1760208270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/14\/8\/854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,29]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["ijerph14080854"],"URL":"https:\/\/doi.org\/10.3390\/ijerph14080854","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,29]]}}}