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PMID: 23643801 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin-vascular endothelial growth factor pathway.

Toxicology and applied pharmacology ·Vol. 271 ·No. 1 ·2013-08-15 ·Pages 20-9

Wang Z, Humphries B, Xiao H, Jiang Y, Yang C

Abstract

Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchial epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that β-catenin was activated in arsenic-transformed cells up-regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic-transformed cells that reversed EMT inhibited β-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown β-catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating β-catenin-VEGF pathway.

Keywords
Angiogenesis Arsenic-transformed cells EMT Epithelial-to-mesenchymal transition (EMT) HUVEC IF MicroRNA-200b (miR-200b) VEGF Wnt epithelial-to-mesenchymal transition human bronchial epithelial cells (HBECs) with p53 expression stably knocked down human umbilical vein endothelial cell immunofluorescence miR-200b microRNA 200b p53(low)HBECs siRNA small interfering RNA vascular endothelial growth factor β-Catenin
MeSH Terms
Animals Arsenic/toxicity Bronchi/cytology,drug effects,metabolism Cell Line Epithelial Cells/drug effects,metabolism Epithelial-Mesenchymal Transition/drug effects Gene Knockdown Techniques Human Umbilical Vein Endothelial Cells Humans Mice Mice, Nude Neovascularization, Pathologic/etiology RNA, Messenger/metabolism RNA, Small Interfering/administration & dosage Reverse Transcriptase Polymerase Chain Reaction Up-Regulation/drug effects Vascular Endothelial Growth Factor A/metabolism beta Catenin/metabolism
Chemicals
RNA, Messenger RNA, Small Interfering Vascular Endothelial Growth Factor A beta Catenin Arsenic
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang Zhishan
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Humphries Brock
Xiao Hua
Jiang Yiguo
Yang Chengfeng
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Article Info
Journal
Toxicology and applied pharmacology
Abbr.
Toxicol Appl Pharmacol
ISSN
1096-0333
DOI
10.1016/j.taap.2013.04.018
Published
2013-08-15
Epub
2013-00-30
Pages
20-9
Language
English
Region
United States
NLM ID
0416575
PMCID
PMC3714366
Subset
IM
Grants
NIEHS NIH HHS · R01 ES017777 · United States
NIEHS NIH HHS · 1R01ES017777-01A1 · United States
External Links
PubMed source DOI: 10.1016/j.taap.2013.04.018 PMC Full Text View journal details
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