ZEB1-responsive genes in non-small cell lung cancer

Abstract The epithelial to mesenchymal transition (EMT) is a developmental process enabling epithelial cells to gain a migratory mesenchymal phenotype. In cancer, this process contributes to metastases; however the regulatory signals and mechanistic details are not fully elucidated. Here, we sought...

Full description

Saved in:
Bibliographic Details
Published in:Cancer letters 2011-01, Vol.300 (1), p.66-78
Main Authors: Gemmill, Robert M, Roche, Joëlle, Potiron, Vincent A, Nasarre, Patrick, Mitas, Michael, Coldren, Chris D, Helfrich, Barbara A, Garrett-Mayer, Elizabeth, Bunn, Paul A, Drabkin, Harry A
Format: Article
Language:English
Subjects:
Blotting, Western
Cadherins - genetics
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell migration
Cloning
Colleges & universities
Cytokines
Deoxyribonucleic acid
DNA
DNA microarrays
E-Cadherin
Epidermal growth factor
Epithelial cells
Epithelial-Mesenchymal Transition
Fibroblast growth factor receptor 1
Gene expression
Genotype & phenotype
Hematology, Oncology and Palliative Medicine
Homeodomain Proteins - analysis
Homeodomain Proteins - genetics
Homeodomain Proteins - physiology
Humans
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Mesenchyme
Metastases
Mortality
N-Cadherin
Non-small cell lung carcinoma
Overexpression
Polymerase chain reaction
Repressor Proteins - analysis
Repressors
Reverse Transcriptase Polymerase Chain Reaction
Serine Endopeptidases - analysis
Transcription
Transcription Factors - analysis
Transcription Factors - genetics
Transcription Factors - physiology
Transforming growth factor- beta
Tumor cell lines
Vimentin
Zinc Finger E-box Binding Homeobox 2
Zinc Finger E-box-Binding Homeobox 1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract The epithelial to mesenchymal transition (EMT) is a developmental process enabling epithelial cells to gain a migratory mesenchymal phenotype. In cancer, this process contributes to metastases; however the regulatory signals and mechanistic details are not fully elucidated. Here, we sought to identify the subset of genes regulated in lung cancer by ZEB1, an E-box transcriptional repressor known to induce EMT. Using an Affymetrix-based expression database of 38 non-small cell lung cancer (NSCLC) cell lines, we identified 324 genes that correlated negatively with ZEB1 and 142 that were positively correlated. A mesenchymal gene pattern (low E-cadherin, high Vimentin or N-cadherin) was significantly associated with ZEB1 and ZEB2, but not with Snail, Slug, Twist1 or Twist2. Among eight genes selected for validation, seven were confirmed to correlate with ZEB1 by quantitative real-time RT-PCR in a series of 22 NSCLC cell lines, either negatively (CDS1, EpCAM, ESRP1, ESRP2, ST14) or positively (FGFR1, Vimentin). In addition, over-expression or knockdown of ZEB1 led to corresponding changes in gene expression, demonstrating that these genes are also regulated by ZEB1, either directly or indirectly. Of note, the combined knockdown of ZEB1 and ZEB2 led to apparent synergistic responses in gene expression. Furthermore, these responses were not restricted to artificial settings, since most genes were similarly regulated during a physiologic induction of EMT by TGF-β plus EGF. Finally, the absence of ST14 (matriptase) was linked to ZEB1 positivity in lung cancer tissue microarrays, implying that the regulation observed in vitro applies to the human disease. In summary, this study identifies a new set of ZEB-regulated genes in human lung cancer cells and supports the hypothesis that ZEB1 and ZEB2 are key regulators of the EMT process in this disease.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2010.09.007