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PMID: 21403400 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice.

The Journal of clinical investigation ·Vol. 121 ·No. 4 ·2011-04-00 ·Pages 1373-85

Yang Y, Ahn YH, Gibbons DL, Zang Y, Lin W, Thilaganathan N, Alvarez CA, Moreira DC, Creighton CJ, Gregory PA, Goodall GJ, Kurie JM

Abstract

Epithelial tumor cells transit to a mesenchymal state in response to extracellular cues, in a process known as epithelial-to-mesenchymal transition (EMT). The precise nature of these cues has not been fully defined, an important issue given that EMT is an early event in tumor metastasis. Here, we have found that a population of metastasis-prone mouse lung adenocarcinoma cells expresses Notch and Notch ligands and that the Notch ligand Jagged2 promotes metastasis. Mechanistically, Jagged2 was found to promote metastasis by increasing the expression of GATA-binding (Gata) factors, which suppressed expression of the microRNA-200 (miR-200) family of microRNAs that target the transcriptional repressors that drive EMT and thereby induced EMT. Reciprocally, miR-200 inhibited expression of Gata3, which reversed EMT and abrogated metastasis, suggesting that Gata3 and miR-200 are mutually inhibitory and have opposing effects on EMT and metastasis. Consistent with this, high levels of Gata3 expression correlated with EMT in primary tumors from 2 cohorts of lung adenocarcinoma patients. These findings reveal what we believe to be a novel Jagged2/miR-200-dependent pathway that mediates lung adenocarcinoma EMT and metastasis in mice and may have implications for the treatment of human epithelial tumors.

MeSH Terms
AC133 Antigen Adenocarcinoma/genetics,metabolism,pathology,secondary Animals Antigens, CD/metabolism Cell Line, Tumor Epithelial-Mesenchymal Transition/genetics,physiology GATA3 Transcription Factor/genetics,metabolism Gene Expression Profiling Glycoproteins/metabolism Humans Jagged-2 Protein Ligands Lung Neoplasms/genetics,metabolism,pathology Membrane Proteins/genetics,metabolism Mice Mice, 129 Strain MicroRNAs/genetics,metabolism Peptides/metabolism Receptors, Notch/metabolism Signal Transduction
Chemicals
AC133 Antigen Antigens, CD GATA3 Transcription Factor Gata3 protein, mouse Glycoproteins Jag2 protein, mouse Jagged-2 Protein Ligands Membrane Proteins MicroRNAs Mirn200 microRNA, mouse Peptides Receptors, Notch
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Yang Yanan
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ahn Young-Ho
Gibbons Don L
Zang Yi
Lin Wei
Thilaganathan Nishan
Alvarez Cristina A
Moreira Daniel C
Creighton Chad J
Gregory Philip A
Goodall Gregory J
Kurie Jonathan M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI42579
Published
2011-04-00
Epub
2011-00-14
Pages
1373-85
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3069760
Subset
IM
Grants
NCI NIH HHS · R01 CA117965 · United States
NCI NIH HHS · P50 CA70907 · United States
NCI NIH HHS · R01 CA132608 · United States
NCI NIH HHS · P50 CA070907 · United States
NCI NIH HHS · T32 CA009666 · United States
NCI NIH HHS · P30 CA125123 · United States
NCI NIH HHS · 5 T32 CA009666 · United States
External Links
PubMed source DOI: 10.1172/JCI42579 PMC Full Text View journal details
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