title: Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin-vascular endothelial growth factor pathway.
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.
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors: Zhishan
authors: Z
authors: Wang
authors: Brock
authors: B
authors: Humphries
authors: Hua
authors: H
authors: Xiao
authors: Yiguo
authors: Y
authors: Jiang
authors: Chengfeng
authors: C
authors: Yang
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000209:etiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D001151:Arsenic
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
references: Toxicol Sci. 2010 May;115(1):214-24
references: 20118188
references: Carcinogenesis. 2011 Mar;32(3):434-42
references: 21173432
references: PLoS One. 2011;6(6):e20858
references: 21687637
references: FASEB J. 2005 Mar;19(3):342-53
references: 15746177
references: Angiogenesis. 2008;11(1):63-9
references: 18253847
references: J Cell Biol. 2006 Mar 27;172(7):973-81
references: 16567498
references: Carcinogenesis. 2012 Jun;33(6):1126-33
references: 22491715
references: Toxicol Sci. 2011 May;121(1):110-22
references: 21292642
references: Toxicol Appl Pharmacol. 2010 May 1;244(3):291-9
references: 20083128
references: Environ Res. 2008 Sep;108(1):48-55
references: 18511031
references: Metallomics. 2012 Jul;4(7):619-27
references: 22473328
references: Toxicol Lett. 2012 Mar 7;209(2):179-85
references: 22230260
references: Environ Health Perspect. 2008 Feb;116(2):158-64
references: 18288312
references: Toxicol Sci. 2012 Dec;130(2):269-80
references: 22872060
references: Nat Med. 2011 Nov 07;17(11):1359-70
references: 22064426
references: Toxicol Sci. 2008 Sep;105(1):24-32
references: 18566022
references: Oncogene. 2013 May 2;32(18):2273-81, 2281e.1-12
references: 22733137
references: Mutat Res. 2006 Jun;612(3):215-246
references: 16574468
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10907-12
references: 9380733
references: Environ Health Perspect. 2012 Jan;120(1):92-7
references: 21954225
references: Biochemistry. 2009 Aug 18;48(32):7705-12
references: 19603745
references: Exp Cell Res. 1998 Aug 1;242(2):419-28
references: 9683529
references: Toxicol Sci. 2003 Dec;76(2):271-9
references: 12970581
references: Nat Cell Biol. 2010 Mar;12(3):247-56
references: 20173740
references: Cell Cycle. 2008 Oct;7(20):3112-8
references: 18927505
references: Cancer Res. 2006 Feb 15;66(4):2116-28
references: 16489012
references: Cell. 2012 Jun 8;149(6):1192-205
references: 22682243
references: Cell. 2009 Nov 25;139(5):871-90
references: 19945376
references: PLoS One. 2012;7(5):e37765
references: 22662215
references: Arch Toxicol. 2013 Jun;87(6):991-1000
references: 23069812
references: Nat Cell Biol. 2008 May;10(5):593-601
references: 18376396
references: PLoS One. 2011;6(10):e25438
references: 21998657
references: J Biol Chem. 2008 May 30;283(22):14910-4
references: 18411277
references: Metallomics. 2011 Nov;3(11):1135-41
references: 21976018
references: Free Radic Biol Med. 2008 Sep 1;45(5):651-8
references: 18572023
references: J Natl Cancer Inst. 2002 Dec 18;94(24):1888-91
references: 12488483
references: Chem Res Toxicol. 2003 Apr;16(4):460-8
references: 12703962