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LKB1 suppresses glioma cell invasion via NF-?B/Snail signaling repression.

ABSTRACT: Background:Liver kinase B1 (LKB1) is involved in various human diseases. Aberrant expression of LKB1 expression is involved in glioma progression and associated with prognosis, however, the specific mechanism involving NF-?B/Snail signaling pathways remain unknown. Materials and methods:In the present study, quantitative real-time PCR analysis was used to investigate the expression of LKB1 tumor tissue samples and cell lines. In glioma cell lines, CCK-8 assay, transwell invasion and migration assays were used to investigate the effects of LKB1on proliferation and invasion. Results:We observed that LKB1 knockdown promoted glioma cell proliferation, migration and invasion. This effect was induced through NF-?B/Snail signaling activation. Also, LKB1 overexpression suppressed proliferation, migration, and invasion, which could be rescued by Snail overexpression. Conclusion:Taken together, our results show that LKB1 knockdown promotes remarkably glioma cell proliferation, migration and invasion by regulating Snail protein expression through activating the NF-?B signaling. This may serve as a potential prognostic marker and therapeutic target for glioma.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC6452796 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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LKB1 suppresses glioma cell invasion via NF-κB/Snail signaling repression.

Yuan Ye Y Li Shi-Lin SL Cao Yu-Lin YL Li Jun-Jun JJ Wang Qiang-Ping QP

OncoTargets and therapy 20190402

<h4>Background</h4>Liver kinase B1 (LKB1) is involved in various human diseases. Aberrant expression of LKB1 expression is involved in glioma progression and associated with prognosis, however, the specific mechanism involving NF-κB/Snail signaling pathways remain unknown.<h4>Materials and methods</h4>In the present study, quantitative real-time PCR analysis was used to investigate the expression of LKB1 tumor tissue samples and cell lines. In glioma cell lines, CCK-8 assay, transwell invasion a ...[more]

PMID: 31040689

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Project description:Melanoma is the most lethal cutaneous cancer with a high metastatic rate worldwide, causing ~55,500 deaths annually. Although the selective B-Raf oncogene serine/threonine-kinase (BRAF) inhibitors, dabrafenib and vemurafenib, have been approved for the treatment of BRAF-mutant metastatic melanoma, the 5-year survival rate remains unfavorable due to acquired therapy resistance. Therefore, it is of great importance to develop alternative therapeutic drugs and uncover their mechanisms for the treatment of melanoma. 7-dehydrocholesterol (7-DHC) has been demonstrated to inhibit melanoma, but the mechanism is unclear. Therefore, the present study aimed to elucidate the mechanisms of the inhibitory effect of 7-DHC in melanoma cells via analyzing the proliferation, migration, apoptosis, cell cycle and transcriptional sequencing of melanoma cells treated with 7-DHC, as well as constructing a gene signature according to public data of patients with melanoma. In the present study, 7-DHC, the precursor of vitamin D3, was able to induce apoptosis and inhibit cell proliferation and invasion of melanoma cells in a dose-dependent manner. RNA sequencing of melanoma cells treated with different concentrations of 7-DHC revealed that, compared with untreated melanoma cells, 65 genes were downregulated, and genes involved in the regulation of NF-ĸB import into the nucleus and NF-ĸB signaling were significantly repressed. Consistently, the Akt kinase family was one of most common somatic mutation hotspots in patients with melanoma according to The Cancer Genome Atlas enrichment analysis. Furthermore, 7-DHC decreased the phosphorylation of Akt1-Ser473 rather than that of MEK1, and the decreased phosphorylation of Akt1 subsequently inhibited the translocation of free RELA proto-oncogene NF-κB subunit to the nucleus. Finally, by intersecting downregulated genes by 7-DHC treatment and upregulated genes in patients with melanoma, a 7-DHC gene signature was identified, which was negatively associated with the prognosis. Overall, the present results demonstrated that 7-DHC suppressed melanoma cell proliferation and invasion via the Akt1/NF-ĸB signaling pathway, and 7-DHC key target genes were negatively associated with the prognosis. These findings highlight the potential application of 7-DHC for the treatment of melanoma in the future.

Project description:BackgroundNumerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The previous studies found that NKILA interacted with and suppressed the nuclear translocation of NF-KappaB, which influenced metastasis and prognosis in breast cancer. However the clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown.MethodsWe examined expression levels of NKILA in 106 pairs of NSCLC tissues and cell lines. The expression level of NKILA after TGF-β1 stimulation also was examined by qRT-PCR and validated by Chromatin immunoprecipitation (ChIP). Gain-of-function and loss-of-function assays were performed to examine the effect of NKILA on proliferation, migration and invasion of NSCLC cells. RNA immunoprecipitation (RIP), western blot and rescue experiments were carried out to reveal the interrelation between NKILA, NF-κB and EMT signal pathway.ResultsThe expression of NKILA was down-regulated in NSCLC cancer tissues compared with matched adjacent noncancerous tissues, and lower NKILA expression in tumor tissues were significantly correlated with lymph node metastasis and advanced TNM stage. We found that the expression of NKILA was mainly regulated by classical TGF-β signal pathway in NSCLC cells rather than NF-κB pathway reported in breast cancer. Gain and loss of function assays found that NKILA inhibited migration, invasion and viability of NSCLC cells. Mechanistic study showed that NKILA attenuated Snail expression via inhibiting the phosphorylation of IκBα and NF-κB activation, subsequently suppressed the expression of markers of epithelial-mesenchymal transition process.ConclusionsThe present study found that the expression of NKILA was downregulated in tumor tissues of NSCLC, which improved the metastasis of NSCLC patients. In vitro studies further clarified that the expression of NKILA was regulated through classical TGF-β signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-κB/Snail signal pathway in NSCLC cells.

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LKB1 suppresses glioma cell invasion via NF-?B/Snail signaling repression.

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LKB1 suppresses glioma cell invasion via NF-κB/Snail signaling repression.

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