Modulation of NCAM/FGFR1 signaling suppresses EMT program in human proximal tubular epithelial cells

Autor: Björn Tampe, Gunsmaa Nyamsuren, Xingbo Xu, Maja Životić, Müller Ca, Aleksandar Lipkovski, Gerhard A. Müller, Jasmina Markovic-Lipkovski, Michael Zeisberg
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cell signaling
Adhesion molecules
Kidneys
Fibrosis
Chronic kidney disease
Gene expression
Epithelial cells
Fibroblast growth factor
Signal initiation
Fibroblast Growth Factor
Physiology
lcsh:Medicine
Gene Expression
MMP9
Signal transduction
Fibroblast growth factor
CDH2
Epithelium
Kidney Tubules
Proximal
0302 clinical medicine
Endocrinology
Animal Cells
Cell Movement
Chronic Kidney Disease
Medicine and Health Sciences
Protein Isoforms
lcsh:Science
Neural Cell Adhesion Molecules
Multidisciplinary
Cell adhesion molecule
Chemistry
Signaling cascades
Middle Aged
3. Good health
Cell biology
Fibroblast growth factor receptor
Nephrology
030220 oncology & carcinogenesis
Kidney Diseases
Anatomy
Cellular Types
Research Article
Adult
Epithelial-Mesenchymal Transition
Adhesion Molecules
Cell Line
Transforming Growth Factor beta1
03 medical and health sciences
Growth Factors
Genetics
Humans
RNA
Messenger
Receptor
Fibroblast Growth Factor
Type 1
Smad3 Protein
Biology and life sciences
Endocrine Physiology
Fibroblast growth factor receptor 1
lcsh:R
Epithelial Cells
Renal System
Molecular Development
stomatognathic diseases
030104 developmental biology
Biological Tissue
Pyrimidines
TGF-beta signaling cascade
SNAI1
lcsh:Q
Neural cell adhesion molecule
Snail Family Transcription Factors
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 13, Iss 11, p e0206786 (2018)
ISSN: 1932-6203
Popis: Neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) cross-talk have been involved in epithelial-to-mesenchymal transition (EMT) process during carcinogenesis. Since EMT also contributes to maladaptive repair and parenchymal damage during renal fibrosis, we became encouraged to explore the role of NCAM/FGFR1 signaling as initiating or driving forces of EMT program in cultured human proximal tubular epithelial cells (TECs). TECs stimulated with TGF-β1 (10ng/mL) was used as an established in vitro EMT model. TGF-β1 downstream effectors were detected in vitro, as well as in 50 biopsies of different human kidney diseases to explore their in vivo correlation. NCAM/FGFR1 signaling and its modulation by FGFR1 inhibitor PD173074 (100nM) were analyzed by light microscopy, immunolabeling, qRT-PCR and scratch assays. Morphological changes associated with EMT appeared 48h after TGF-ß1 treatment and was clearly apparent after 72 hours, followed by loss of CDH1 (encoding E-Cadherin) and transcriptional induction of SNAI1 (SNAIL), SNAI2 (SLUG), TWIST1, MMP2, MMP9, CDH2 (N-Cadherin), ITGA5 (integrin-α5), ITGB1 (integrin-β1), ACTA2 (α-SMA) and S100A4 (FSP1). Moreover, at the early stage of EMT program (24 hours upon TGF-β1 exposure), transcriptional induction of several NCAM isoforms along with FGFR1 was observed, implicating a mechanistic link between NCAM/FGFR1 signaling and induction of EMT. These assumptions were further supported by the inhibition of the EMT program after specific blocking of FGFR1 signaling by PD173074. Finally, there was evidence for an in vivo TGF-β1 pathway activation in diseased human kidneys and correlation with impaired renal excretory functions. Collectively, NCAM/FGFR1 signaling appears to be involved in the initial phase of TGF-ß1 initiated EMT which can be effectively suppressed by application of FGFR inhibitor. peerReviewed
Databáze: OpenAIRE
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