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Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-beta signaling

Title
Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-beta signaling
Authors
Kaowinn, SirichatKim, JeonghyoLee, JaebeomShin, Dong HoonKang, Chi-DugKim, Dae-KeeLee, SoojinKang, Min KyungKoh, Sang SeokKim, Seong-JinChung, Young-Hwa
Ewha Authors
김대기
SCOPUS Author ID
김대기scopus
Issue Date
2017
Journal Title
ONCOTARGET
ISSN
1949-2553JCR Link
Citation
vol. 8, no. 3, pp. 5092 - 5110
Keywords
CUG2TGF-betaEMTSp1Smad2/3
Publisher
IMPACT JOURNALS LLC
Indexed
SCIE; SCOPUS WOS scopus
Abstract
Cancer upregulated gene 2 (CUG2) enhances cell migration and invasion, but the underlying mechanism has not been revealed. Herein, CUG2 decreased the expression of E-cadherin and increased the expression of N-cadherin and vimentin, characteristics of the epithelial-mesenchymal transition (EMT). A CUG2 deletion mutant, lacking interaction with nucleophosmin 1 (NPM1), or suppression of NPM1 reduced wound healing and cell invasion, indicating that CUG2-mediated EMT requires NPM1. CUG2 enhanced activation of Smad2/3 and expression of Snail and Twist, while the CUG2 silence decreased these TGF-beta signaling pathways, leading to suppression of EMT. NPM silence also inhibited the CUG2-induced TGF-beta signaling. These results suggest that TGF-beta signaling is involved in CUG2-induced EMT. Treatment with EW-7197, a novel inhibitor of TGF-beta signaling, diminished CUG2-mediated EMT and inhibition of Akt, ERK, JNK, and p38 MAPK, non-canonical TGF-beta signaling molecules, also decreased expression of Smad2/3, Snail and Twist, leading to inhibition of EMT. The results confirm that TGF-beta signaling is essential for CUG2-mediated EMT. Interestingly, TGF-beta enhanced CUG2 expression. We further found that both CUG2-induced TGF-beta production and TGF-beta-induced CUG2 up-regulation required a physical interaction between Sp1 and Smad2/3 in the CUG2 and TGF-beta promoter, as demonstrated by a promoter reporter assay, immunoprecipitation, and ChIP assay. These results indicated close crosstalk between CUG2 and TGF-beta. Conversely, suppression of CUG2 or NPM1 did not completely inhibit TGF-beta-induced EMT, indicating that the effect of TGF-beta on EMT is dominant over the effect of CUG2 on EMT. Collectively, our findings suggest that CUG2 induces the EMT via TGF-beta signaling.
DOI
10.18632/oncotarget.13867
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약학대학 > 약학과 > Journal papers
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