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

ABSTRACT: NF-?B has 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-?B signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-?B activity was accomplished through the specific NF-?B inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKB? repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-?B decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and 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-?B inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-?B signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, 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-?B signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

SUBMITTER: Nomura A

PROVIDER: S-EPMC5121017 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Nomura Alice A Majumder Kaustav K Giri Bhuwan B Dauer Patricia P Dudeja Vikas V Roy Sabita S Banerjee Sulagna S Saluja Ashok K AK

Laboratory investigation; a journal of technical methods and pathology 20161024 12

NF-κB has 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 ...[more]

PMID: 27775688

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Project description:The long non-coding RNA (lncRNA) NF-?B interaction lncRNA (NKILA) has been found to exert tumor suppressive effects in numerous types of carcinoma; however, the relationship between NKILA and cervical cancer (CC) remains largely unclear. The present study aimed to investigate the effects of NKILA on the proliferation and metastasis of CC cell lines, in addition to the related molecular mechanisms. Reverse transcription-quantitative PCR was used to detect the expression levels of NKILA in cancer tissues and cell lines. The constructed overexpression vector, pcDNA3.1NKILA, and its corresponding negative control sequence were transfected into CaSki cells and short hairpin RNA targeting NKILA and the corresponding negative control sequence were transfected into C-33A cells. Subsequently, the proliferative, migratory and invasive ability, as well as the process of epithelial-mesenchymal transition (EMT) of C-33 A and CaSki cells were analyzed by performing Cell Counting Kit-8, wound healing, Matrigel invasion and western blot assays, respectively. The expression levels of proteins were detected using western blot analysis. The expression levels of NKILA were decreased in CC tissues and CC cell lines (SiHa, C-33A, CaSki and HeLa) and the downregulation of NKILA expression using shRNA was observed to significantly increase the proliferation of CC cells. Conversely, the upregulation of NKILA inhibited the proliferation of CC cells, in addition to significantly inhibiting the migration and invasion of CaSki cells, whereas the knockdown of NKILA promoted the invasion of C-33A cells. Thus, it was hypothesized that NKILA may inhibit the migration and invasion of CC cells via regulation of EMT processes, which was reflected by the expression of ZO-1, E-cadherin, N-cadherin and Vimentin. Furthermore, the overexpression of NKILA significantly inhibited the activation of NF-?B in CaSki cells, whereas the knockdown of NKILA expression promoted the degradation of inhibitory protein-?B and promoted the transfer of p65 into the nucleus in C-33A cells. In conclusion, the results from the present study suggested that NKILA may be involved in the inhibition of migration and invasion in CC cells through regulating EMT processes, which may be related to its inhibition of NF-?B activation.

Dataset Information

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

Publications

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

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