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Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide.

Ge D, Jing Q, Zhao W, Yue H, Su L, Zhang S, Zhao J - PLoS ONE (2014)

Bottom Line: Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h.Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly.The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO.

View Article: PubMed Central - PubMed

Affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China.

ABSTRACT
Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

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Microarray assay of gene expression induced by 50 µg/ml of SFO in medium for 6 h.(A) Scatter plot of differentially expressed genes. (B) The 13 genes with more than eight-fold change in expression and ATF4 on microarray analysis. The microarray results represent a single experiment.
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pone-0099378-g003: Microarray assay of gene expression induced by 50 µg/ml of SFO in medium for 6 h.(A) Scatter plot of differentially expressed genes. (B) The 13 genes with more than eight-fold change in expression and ATF4 on microarray analysis. The microarray results represent a single experiment.

Mentions: To understand the molecular mechanism by which SFO induces EndoMT, we first found the candidates that were implicated in the EndoMT. On microarray assay, 717 genes showed changed expression (>1.5-fold) during EndoMT induced by treatment with SFO, 50 µg/ml, for 6 h; 13 genes showed > eight-fold changed expression (Fig. 3). The greatly increased expression of ATF4, p75NTR and IL-8 (CXCL1 in mouse) was verified by qPCR and western blot assay in HUVECs and endothelial MS1 cells (Fig. 4).


Finding ATF4/p75NTR/IL-8 signal pathway in endothelial-mesenchymal transition by safrole oxide.

Ge D, Jing Q, Zhao W, Yue H, Su L, Zhang S, Zhao J - PLoS ONE (2014)

Microarray assay of gene expression induced by 50 µg/ml of SFO in medium for 6 h.(A) Scatter plot of differentially expressed genes. (B) The 13 genes with more than eight-fold change in expression and ATF4 on microarray analysis. The microarray results represent a single experiment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048316&req=5

pone-0099378-g003: Microarray assay of gene expression induced by 50 µg/ml of SFO in medium for 6 h.(A) Scatter plot of differentially expressed genes. (B) The 13 genes with more than eight-fold change in expression and ATF4 on microarray analysis. The microarray results represent a single experiment.
Mentions: To understand the molecular mechanism by which SFO induces EndoMT, we first found the candidates that were implicated in the EndoMT. On microarray assay, 717 genes showed changed expression (>1.5-fold) during EndoMT induced by treatment with SFO, 50 µg/ml, for 6 h; 13 genes showed > eight-fold changed expression (Fig. 3). The greatly increased expression of ATF4, p75NTR and IL-8 (CXCL1 in mouse) was verified by qPCR and western blot assay in HUVECs and endothelial MS1 cells (Fig. 4).

Bottom Line: Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h.Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly.The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO.

View Article: PubMed Central - PubMed

Affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China.

ABSTRACT
Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

Show MeSH
Related in: MedlinePlus