Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.4300
Title: Functional relevance of a six mesenchymal gene signature in epithelial-mesenchymal transition (EMT) reversal by the triple angiokinase inhibitor, nintedanib (BIBF1120)
Authors: Huang, R.Y.-J 
Kuay, K.T 
Tan, T.Z 
Asad, M
Tang, H.M 
Chun Ng, A.H 
Ye, J 
Chung, V.Y 
Thiery, J.P 
Keywords: nintedanib
saracatinib
small interfering RNA
transcription factor ZEB1
uvomorulin
antineoplastic agent
enzyme inhibitor
indole derivative
nintedanib
animal experiment
animal model
animal tissue
antineoplastic activity
Article
CD99L2 gene
cell proliferation
controlled study
cytotoxicity
down regulation
EMP3 gene
epithelial mesenchymal transition
female
gene
gene expression
gene identification
gene silencing
human
human cell
in vitro study
in vivo study
ITGA5 gene
mouse
nonhuman
ovarian cancer cell line
protein expression
SYDE1 gene
upregulation
VIM gene
ZEB1 gene
animal
Bagg albino mouse
drug effects
epithelial mesenchymal transition
genetics
metabolism
nude mouse
Ovarian Neoplasms
pathology
treatment outcome
tumor cell line
Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Enzyme Inhibitors
Epithelial-Mesenchymal Transition
Female
Humans
Indoles
Mice
Mice, Inbred BALB C
Mice, Nude
Ovarian Neoplasms
Treatment Outcome
Issue Date: 2015
Citation: Huang, R.Y.-J, Kuay, K.T, Tan, T.Z, Asad, M, Tang, H.M, Chun Ng, A.H, Ye, J, Chung, V.Y, Thiery, J.P (2015). Functional relevance of a six mesenchymal gene signature in epithelial-mesenchymal transition (EMT) reversal by the triple angiokinase inhibitor, nintedanib (BIBF1120). Oncotarget 6 (26) : 22098-22113. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.4300
Abstract: Epithelial-mesenchymal transition (EMT), a crucial mechanism in carcinoma progression, describes the process whereby epithelial cells lose their apico-basal polarity and junctional complexes and acquire a mesenchymal-like morphology. Several markers are considered to be authentic indicators of an epithelial or mesenchymal status; however, there is currently no comprehensive or systematic method with which to determine their functional relevance. Previously, we identified a 33-gene EMT signature comprising 25 epithelial and 6 mesenchymal genes that best describe this concept of the EMT spectrum. Here, we designed small-scale siRNA screens targeting these six mesenchymal signature genes (CD99L2, EMP3, ITGA5, SYDE1, VIM, ZEB1) to explore their functional relevance and their roles during EMT reversal by nintedanib (BIBF1120) in a mesenchymal-like SKOV3 ovarian cancer cell line. We found that neither cell proliferation nor cytotoxicity was affected by silencing any of these genes. SKOV3 cells expressing siRNA against mesenchymal genes (ZEB1, EMP3, CD99L2, ITGA5, and SYDE1) showed enhanced colony compaction (reduced inter-nuclear distance). Inductions of E-cadherin expression were only observed in SYDE1- and ZEB1-silenced SKOV3 cells. In addition, only SYDE1-silenced SKOV3 cells showed increased anoikis. Finally, we identified that SYDE1 and ZEB1 were down-regulated in nintedanib-treated SKOV3 cells and SYDE1- and ZEB1-silenced SKOV3 cells showed enhanced nintedanib-induced up-regulation of E-cadherin. Nintedanib-treated SKOV3 cells also showed colony compaction and decreases in EMT scores both in vitro and in vivo. We conclude that SYDE1 and ZEB1 are functionally relevant in EMT reversal. This study thus provides a proof-of-concept for the use of in vitro siRNA screening to explore the EMT-related functions of selected genes and their potential relevance in the discovery of EMT reversing drugs.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174142
ISSN: 19492553
DOI: 10.18632/oncotarget.4300
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