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2017 ; 1
(1
): 2
Nephropedia Template TP
Jia D
; Jolly MK
; Tripathi SC
; Den Hollander P
; Huang B
; Lu M
; Celiktas M
; Ramirez-Peña E
; Ben-Jacob E
; Onuchic JN
; Hanash SM
; Mani SA
; Levine H
Cancer Converg
2017[]; 1
(1
): 2
PMID29623961
show ga
BACKGROUND: The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking
cells with enhanced migratory ability during embryonic development and tissue
repair. EMT can also be co-opted by cancer cells to acquire metastatic potential
and drug-resistance. Recent research has argued that epithelial (E) cells can
undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M)
phenotype that typically displays collective migration, or a complete EMT to
adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT
regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various
studies, but how this network regulates the transitions among the E, E/M, and M
phenotypes remains controversial. Two major mathematical models - ternary chimera
switch (TCS) and cascading bistable switches (CBS) - that both focus on the
miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT
dynamics, but a detailed analysis of how well either or both of these two models
can capture recent experimental observations about EMT dynamics remains to be
done. RESULTS: Here, via an integrated experimental and theoretical approach, we
first show that both these two models can be used to understand the two-step
transition of EMT - E?E/M?M, the different responses of SNAIL and ZEB1 to
exogenous TGF-? and the irreversibility of complete EMT. Next, we present new
experimental results that tend to discriminate between these two models. We show
that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and
that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in
the absence of ZEB1 and FOXC2. CONCLUSIONS: These experimental results argue in
favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way
decision-making switch enabling transitions among the E, hybrid E/M and M
phenotypes.
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