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Toxicol Appl Pharmacol. 2016 May 1;298:48-55. doi: 10.1016/j.taap.2016.03.005. Epub 2016 Mar 10.

TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling.

Author information

1
School of Public Health, Xinxiang Medical University, 453003, China; The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
2
School of Public Health, Xinxiang Medical University, 453003, China.
3
Medical College, Henan University of Science & Technology, 471023, China.
4
The Fifth Affiliated Hospital, Zhengzhou University, 450052, China.
5
School of Public Health, Xinxiang Medical University, 453003, China; School of Public Health, Zhengzhou University, 450001, China. Electronic address: zly@zzu.edu.cn.

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.

KEYWORDS:

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Cleft palate; EGFR/ERK pathway; Epithelial-mesenchymal transition (EMT); Human fetal palatal epithelial cells (hFPECs)

PMID:
26971374
DOI:
10.1016/j.taap.2016.03.005
[Indexed for MEDLINE]

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