title: TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling.
abstract: One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFβ3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD.
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China; The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Bu
authors.affiliation: Medical College, Henan University of Science & Technology, 471023, China.
authors.forename: Xiaozhuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Xugang
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Guofu
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Erhui
authors.initials: E
authors.lastname: Wang
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Shibin
authors.initials: S
authors.lastname: Ding
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China.
authors.forename: Ruling
authors.initials: R
authors.lastname: Shi
authors.affiliation: The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
authors.forename: Qiaoyun
authors.initials: Q
authors.lastname: Li
authors.affiliation: The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Fu
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, China; School of Public Health, Zhengzhou University, 450001, China. Electronic address: zly@zzu.edu.cn.
authors.forename: Zengli
authors.initials: Z
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010159:Palate / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D061251:Primary Cell Culture; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Cleft palate; EGFR/ERK pathway; Epithelial-mesenchymal transition (EMT); Human fetal palatal epithelial cells (hFPECs)