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2014 ; 3
(1
): 28
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gab.com Text
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English Wikipedia
Transcriptional factor snail controls tumor neovascularization, growth and
metastasis in mouse model of human ovarian carcinoma
#MMPMID26932374
Abdulkhalek S
; Geen OD
; Brodhagen L
; Haxho F
; Alghamdi F
; Allison S
; Simmons DJ
; O'Shea LK
; Neufeld RJ
; Szewczuk MR
Clin Transl Med
2014[Dec]; 3
(1
): 28
PMID26932374
show ga
BACKGROUND: Snail, a transcriptional factor and repressor of E-cadherin is well
known for its role in cellular invasion. It can regulate epithelial to
mesenchymal transition (EMT) during embryonic development and in epithelial
cells. Snail also mediates tumor progression and metastases. Silencing of Snail
and its associate member Slug in human A2780 ovarian epithelial carcinoma cell
line was investigated to identify its role in tumor neovascularization. METHODS:
Live cell sialidase, WST-1 cell viability and immunohistochemistry assays were
used to evaluate sialidase activity, cell survival and the expression levels of
tumor E-cadherin, N-cadherin, VE-cadherin, and host endothelial CD31+(PECAM-1)
cells in archived paraffin-embedded ovarian A2780, A2780 Snail shRNA GIPZ
lentiviral knockdown (KD) and A2780 Slug shRNA GIPZ lentiviral KD tumors grown in
RAGxC? double mutant mice. RESULTS: Oseltamivir phosphate (OP), anti-Neu1
antibodies and MMP-9 specific inhibitor blocked Neu1 activity associated with
epidermal growth factor (EGF) stimulated A2780 ovarian epithelial carcinoma
cells. Silencing Snail in A2780 cells abrogated the Neu1 activity following EGF
stimulation of the cells compared to A2780 and A2780 Slug KD cells. OP treatment
of A2780 and cisplatin-resistant A2780cis cells reproducibly and dose-dependently
abated the cell viability with a LD50 of 7 and 4 ?m, respectively, after 48 h of
incubation. Heterotopic xenografts of A2780 and A2780 Slug KD tumors developed
robust and bloody tumor vascularization in RAG2xC? double mutant mice. OP
treatment at 50 mg/kg daily intraperitoneally did not significantly impede A2780
tumor growth rate but did cause a significant reduction of lung metastases
compared with the untreated and OP 30mg/kg cohorts. Silencing Snail in A2780
tumor cells completely abrogated tumor vascularization, tumor growth and spread
to the lungs in RAGxC? double mutant mice. A2780 and A2780 Slug KD tumors
expressed high levels of human N- and VE-cadherins, and host CD31+ endothelial
cells, while A2780 Snail KD tumors expressed E-cadherin and reduced host CD31+
cells. OP 50mg/kg cohort tumors had reduced numbers of host CD31+ cells compared
to a higher expression levels of CD31+ cells in tumors from the untreated control
and OP 30mg/kg cohorts. CONCLUSION: Snail transcriptional factor is an important
intermediate player in human ovarian tumor neovascularization.