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2015 ; 16
(1
): 529
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Analysis of the TGF?-induced program in primary airway epithelial cells shows
essential role of NF-?B/RelA signaling network in type II epithelial mesenchymal
transition
#MMPMID26187636
Tian B
; Li X
; Kalita M
; Widen SG
; Yang J
; Bhavnani SK
; Dang B
; Kudlicki A
; Sinha M
; Kong F
; Wood TG
; Luxon BA
; Brasier AR
BMC Genomics
2015[Jul]; 16
(1
): 529
PMID26187636
show ga
BACKGROUND: The airway epithelial cell plays a central role in coordinating the
pulmonary response to injury and inflammation. Here, transforming growth factor-?
(TGF?) activates gene expression programs to induce stem cell-like properties,
inhibit expression of differentiated epithelial adhesion proteins and express
mesenchymal contractile proteins. This process is known as epithelial mesenchymal
transition (EMT); although much is known about the role of EMT in cellular
metastasis in an oncogene-transformed cell, less is known about Type II EMT, that
occurring in normal epithelial cells. In this study, we applied next generation
sequencing (RNA-Seq) in primary human airway epithelial cells to understand the
gene program controlling Type II EMT and how cytokine-induced inflammation
modifies it. RESULTS: Generalized linear modeling was performed on a two-factor
RNA-Seq experiment of 6 treatments of telomerase immortalized human small airway
epithelial cells (3 replicates). Using a stringent cut-off, we identified 3,478
differentially expressed genes (DEGs) in response to EMT. Unbiased transcription
factor enrichment analysis identified three clusters of EMT regulators, one
including SMADs/TP63 and another NF-?B/RelA. Surprisingly, we also observed 527
of the EMT DEGs were also regulated by the TNF-NF-?B/RelA pathway. This Type II
EMT program was compared to Type III EMT in TGF? stimulated A549 alveolar lung
cancer cells, revealing significant functional differences. Moreover, we observe
that Type II EMT modifies the outcome of the TNF program, reducing IFN signaling
and enhancing integrin signaling. We confirmed experimentally that TGF?-induced
the NF-?B/RelA pathway by observing a 2-fold change in NF-?B/RelA nuclear
translocation. A small molecule IKK inhibitor blocked TGF?-induced core
transcription factor (SNAIL1, ZEB1 and Twist1) and mesenchymal gene (FN1 and VIM)
expression. CONCLUSIONS: These data indicate that NF-?B/RelA controls a
SMAD-independent gene network whose regulation is required for initiation of Type
II EMT. Type II EMT dramatically affects the induction and kinetics of
TNF-dependent gene networks.