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Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer

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ABSTRACT

NF-κB plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

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Inhibition of NF-κB in PDAC decreases EMT related marker expression in vivo: Minnelide treatment in patient derived xenografts decreased (a) EMT gene expression and (b) mesenchymal marker expression as well as in KPC tumors (c) and (d), respectively. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
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Figure 3: Inhibition of NF-κB in PDAC decreases EMT related marker expression in vivo: Minnelide treatment in patient derived xenografts decreased (a) EMT gene expression and (b) mesenchymal marker expression as well as in KPC tumors (c) and (d), respectively. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.

Mentions: Early gene expression changes with Minnelide treatment in a human tumor xenograft model were assessed at 7 days after start of treatment. EMT associated genes, upregulated during this transition were decreased significantly with Minnelide treatment. EMT inducing transcription factors: SNAI1 (0.503 ± 0.070 fold), SNAI2 (0.408 ± 0.061 fold), and ZEB1 (0.350 ± 0.060 fold) were significantly down regulated. MMP9, VIM, and CDH2 decreased to 0.227 ± 0.063, 0.569 ±0.061, and 0.539 ± 0.056 of saline control, respectively (Figure 3a).


Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer
Inhibition of NF-κB in PDAC decreases EMT related marker expression in vivo: Minnelide treatment in patient derived xenografts decreased (a) EMT gene expression and (b) mesenchymal marker expression as well as in KPC tumors (c) and (d), respectively. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121017&req=5

Figure 3: Inhibition of NF-κB in PDAC decreases EMT related marker expression in vivo: Minnelide treatment in patient derived xenografts decreased (a) EMT gene expression and (b) mesenchymal marker expression as well as in KPC tumors (c) and (d), respectively. Each bar is representative of three or more independent experiments; error bars are represented in SEM; and the asterisk (*) indicates a p value < 0.05.
Mentions: Early gene expression changes with Minnelide treatment in a human tumor xenograft model were assessed at 7 days after start of treatment. EMT associated genes, upregulated during this transition were decreased significantly with Minnelide treatment. EMT inducing transcription factors: SNAI1 (0.503 ± 0.070 fold), SNAI2 (0.408 ± 0.061 fold), and ZEB1 (0.350 ± 0.060 fold) were significantly down regulated. MMP9, VIM, and CDH2 decreased to 0.227 ± 0.063, 0.569 ±0.061, and 0.539 ± 0.056 of saline control, respectively (Figure 3a).

View Article: PubMed Central - PubMed

ABSTRACT

NF-&kappa;B plays an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study we demonstrate the importance of activated NF-&kappa;B signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-&kappa;B activity was accomplished through the specific NF-&kappa;B inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKB&alpha; repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-&kappa;B decreased the expression of several EMT transcription factors (SNAI1, SNAI2, ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-&kappa;B inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreased overall metastasis. Furthermore, we demonstrate the importance of active NF-&kappa;B signaling in neural invasion. Triptolide treatment inhibits NGF mediated and neural-tumor co-culture in vitro invasion and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-&kappa;B signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

No MeSH data available.


Related in: MedlinePlus