The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200–dependent pathway in mice
Yanan Yang, … , Gregory J. Goodall, Jonathan M. Kurie
Yanan Yang, … , Gregory J. Goodall, Jonathan M. Kurie
Published March 14, 2011
Citation Information: J Clin Invest. 2011;121(4):1373-1385. https://doi.org/10.1172/JCI42579.
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Research Article Oncology

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

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.

Authors

Yanan Yang, Young-Ho Ahn, Don L. Gibbons, Yi Zang, Wei Lin, Nishan Thilaganathan, Cristina A. Alvarez, Daniel C. Moreira, Chad J. Creighton, Philip A. Gregory, Gregory J. Goodall, Jonathan M. Kurie

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Figure 3

Characterization of Jagged-depleted 344SQ cells.

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Characterization of Jagged-depleted 344SQ cells. (A and B) Jagged deplet...
(A and B) Jagged depletion inactivates Notch. Quantification of (A) Jag1 and (B) Jag2 mRNA by quantitative PCR (bar graph) and Notch activation by Western blotting of cleaved Notch1 (gels) in Jagged1-depleted (Jag1 KD), Jagged2-depleted (Jag2 KD), and control (Scr) 344SQ transfectants. Quantitative PCR values were normalized based on L32 mRNA and expressed as the mean values of replicate (triplicate) samples relative to that of controls, which were set at 1.0. Actin indicates relative protein loading. (C and D) Jagged depletion has no effect on 344SQ cell proliferation. Quantification of (C) Jagged1-depleted and (D) Jagged2-depleted 344SQ cells grown in monolayer, counted at the indicated time points and expressed as the mean values (± SD) of replicate (triplicate) wells. (E and F) Inhibition of 344SQ cell migration and invasion by depletion of Jagged2 but not Jagged1. Images of migrated (top rows) and invaded (bottom rows) (E) Jagged1-depleted, (F) Jagged2-depleted, and (E and F) control 344SQ cells, which were counted and expressed as the mean values (± SD) of replicate (triplicate) wells (bar graphs), with P values from Welch’s t test using log-transformed data. Scale bars: 100 μm.