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Long Non-Coding RNA NKILA Reduces Oral Squamous Cell Carcinoma Development Through the NF-KappaB Signaling Pathway.

ABSTRACT: OBJECTIVE:Emerging studies have identified that long non-coding RNAs (lncRNAs) play critical roles in cancer development. This study aims to explore the mechanism of NF-KappaB (NF-?B) interacting lncRNA (NKILA) in the pathological process of oral squamous cell carcinoma (OSCC). METHODS:NKILA expression in OSCC tissues, paracancerous tissues, and normal human oral keratinocytes and OSCC cell lines was detected using RT-qPCR. KB cells were selected for the follow-up experiments. The role of NKILA in cell proliferation, migration, invasion, and NF-?B signaling pathway was identified using the gain- and loss-of function of NKILA in OSCC cells. Additionally, the role of NKILA in vitro was determined by inducing xenograft tumors in nude mice. RESULTS:NKILA was poorly expressed in OSCC tissues and cells. Cell proliferation, invasion and migration, tumor volume and weight were significantly suppressed in cells with overexpressed NKILA, while silencing NKILA led to opposite trends. Moreover, the protein levels of p-I?B? and nuclear-p65 were markedly decreased, while the levels of I?B? and cytoplasm-p65 were enhanced in cells with overexpressed NKILA. CONCLUSION:This study provided evidence that NKILA could reduce proliferation, invasion and migration of OSCC cells through inhibiting the NF-?B signaling pathway. The findings may offer new insights for OSCC prevention and treatment.

SUBMITTER: Hu D

PROVIDER: S-EPMC7645807 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Long Non-Coding RNA NKILA Reduces Oral Squamous Cell Carcinoma Development Through the NF-KappaB Signaling Pathway.

Hu Daoyong D Zhong Tian T Dai Qun Q

Technology in cancer research & treatment 20200101

<h4>Objective</h4>Emerging studies have identified that long non-coding RNAs (lncRNAs) play critical roles in cancer development. This study aims to explore the mechanism of NF-KappaB (NF-κB) interacting lncRNA (NKILA) in the pathological process of oral squamous cell carcinoma (OSCC).<h4>Methods</h4>NKILA expression in OSCC tissues, paracancerous tissues, and normal human oral keratinocytes and OSCC cell lines was detected using RT-qPCR. KB cells were selected for the follow-up experiments. The ...[more]

PMID: 33143574

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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-?1 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-?B 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-? signal pathway in NSCLC cells rather than NF-?B 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 I?B? and NF-?B 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-? signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-?B/Snail signal pathway in NSCLC cells.

Project description:Long non?coding RNAs (lncRNAs) have been consistently demonstrated to be involved in oral squamous cell carcinoma (OSCC) as either tumor oncogenes or tumor suppressors. However, the underlying mechanisms of OSCC tumorigenesis and development have not yet been fully elucidated. The expression profiles of mRNAs and lncRNAs in OSCC were analyzed by a microarray assay. To verify the results of the microarray, 10 differentially expressed lncRNAs were randomly selected and measured by quantitative RT?PCR (qRT?PCR). Gene Ontology (GO) and metabolic pathway analyses were performed to analyze gene function and identify enriched pathways. Subsequently, two independent algorithms were used to predict the target genes of the lncRNAs. We identified 2,294 lncRNAs and 1,938 mRNAs that were differentially expressed in all three OSCC tissues by a microarray assay. Through the construction of co?expression networks of differentially expressed genes, 4 critical lncRNAs nodes were identified as potential key factors in the pathogenesis of OSCC. Expression of the 4 critical lncRNA nodes was not associated with age, sex, smoking or tumor location (P>0.05) but was positively correlated with clinical stage, lymphatic metastasis, distant metastasis and survival status (P<0.05). Kaplan?Meier analysis demonstrated that low expression levels of these 4 critical lncRNA nodes contributed to poor median progression?free survival (PFS) and overall survival (OS) (P<0.05). GO and pathway analyses indicated that the functions and enriched pathways of many dysregulated genes are associated with cancer. Potential target genes of dysregulated lncRNAs were enriched in 43 metabolic pathways, with cancer pathways being the primary enrichment pathways. In summary, we analyzed the profile of lncRNAs in OSCC and identified the functions and enriched metabolic pathways of both dysregulated mRNAs and the target genes of dysregulated lncRNAs, providing new insights into molecular markers and therapeutic targets for OSCC.

Project description:Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide, due to poor diagnosis and treatment. There is increasing evidence that demonstrates the involvement of long non-coding RNAs (lncRNAs) in carcinogenesis and cancer progression. Therefore, the aim of the present study was to explore potential lncRNA-associated features of patients with OSCC as a valuable and independent prognostic biomarker. A total of 268 lncRNA expression profiles and clinical patient information on OSCC were downloaded from The Cancer Genome Atlas database. The clinical information was exploited for prescreening, using Cox regression analysis, and differentially expressed lncRNAs (DElncRNAs) were identified using edgeR software. Using the 'caret' package, the datasets were categorized into test datasets and training datasets, respectively. Through bioinformatics, seven prognostic DElncRNAs were selected. Using the regression coefficients, a risk score based on the seven-DElncRNA signature was developed to assess the prognostic function of key DElncRNAs. According to the median risk score, patients were classified into high-risk and low-risk groups in the training and test datasets. Additionally, receiver operating characteristic (ROC) curve analysis was conducted to evaluate the sensitivity and specificity of the prognostic DElncRNAs, and the optimal cut-off point was obtained from ROC analysis. Based on the optimal cut-off point, the patients were also categorized into high-risk and low-risk groups. Notably, the optimal cut-off point was more sensitive than the median risk score, particularly in the test dataset. The Kaplan-Meier survival and log rank test analysis results indicated that the P-value, based on the optimal cut-off, was less than the median risk cut-off. Additionally, stratified analysis results revealed that the seven-DElncRNAs signature was also independent of OSCC age. Furthermore, the findings of the present study suggested that the seven-DElncRNA signature can be used as a potential prognostic indicator and may have important clinical significance in OSCC.

Dataset Information

Long Non-Coding RNA NKILA Reduces Oral Squamous Cell Carcinoma Development Through the NF-KappaB Signaling Pathway.

Publications

Long Non-Coding RNA NKILA Reduces Oral Squamous Cell Carcinoma Development Through the NF-KappaB Signaling Pathway.

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