Dataset Information

High expression of Fibronectin 1 suppresses apoptosis through the NF-?B pathway and is associated with migration in nasopharyngeal carcinoma.

ABSTRACT: Fibronectin 1 (FN1) is a member of the glycoprotein family located on chromosome 2q35. It has been reported that FN1 is upregulated in many tumors, and its expression is negatively related to the prognosis and survival of cancer patients. Through data analysis, we found that FN1 is upregulated in nasopharyngeal carcinoma (NPC). This study aimed to investigate how FN1 expression affects NPC cell behavior. In this study, we downregulated FN1 in two NPC cell lines, 5-8F (EBV-) and C666-1 (EBV+), and evaluated invasion, migration and apoptosis. FN1 promoted migration and invasion by upregulating MMP9 and MMP2 expression; the NF-?B/P65 signaling pathway was also affected by FN1. FN1 suppressed apoptosis in NPC cells by upregulating BCL2 and increasing the nuclear localization of P65, both by inducing cytosolic accumulation and nuclear translocation, but FN1 expression was not reduced when the NF-?B/P65 pathway was inhibited in the negative control (NC) group. Compared with NC cells, shFN1 cells showed little change in apoptosis when the NF-?B/P65 pathway was activated by LPS. These results suggest that FN1 regulates apoptosis though P65 in the NF-?B pathway. Our results show that FN1 plays an important role in NPC cells and is a potential target for NPC treatment.

SUBMITTER: Wang J

PROVIDER: S-EPMC5666059 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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High expression of Fibronectin 1 suppresses apoptosis through the NF-κB pathway and is associated with migration in nasopharyngeal carcinoma.

Wang Jinting J Deng Lian L Huang Junpeng J Cai Rui R Zhu Xiongjie X Liu Faquan F Wang Qien Q Zhang Jiren J Zheng Yanfang Y

American journal of translational research 20171015 10

Fibronectin 1 (FN1) is a member of the glycoprotein family located on chromosome 2q35. It has been reported that FN1 is upregulated in many tumors, and its expression is negatively related to the prognosis and survival of cancer patients. Through data analysis, we found that FN1 is upregulated in nasopharyngeal carcinoma (NPC). This study aimed to investigate how FN1 expression affects NPC cell behavior. In this study, we downregulated FN1 in two NPC cell lines, 5-8F (EBV-) and C666-1 (EBV+), an ...[more]

PMID: 29118912

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Project description:BackgroundNasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl-DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was down-regulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types.MethodsRERG expression was assessed in human subjects (NPC primary tissues and non-cancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5-Aza-2'-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines.ResultsRERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERG methylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818-0.976). The down-regulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity, migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with down-regulation of MMPs and IL8 in tumors of nude mouse xenografts.ConclusionsOur results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF-κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.

Project description:To screen microRNAs (miRNAs) and analyze their role in the nasopharyngeal carcinoma (NPC) development through differential analysis and cytological validation of the nasopharyngeal carcinoma dataset. The Gene Expression Omnibus (GEO) database of NPC-related data were utilized to screen for differential miRNAs, downstream target genes and relevant pathways, and the relationships among them were verified by luciferase reporter assay and cell co-culture. To analyze the function of miRNAs and downstream target genes, a series of mimics, inhibitors or Small interfering RNAs (siRNAs) targeting the downstream target genes were transfected into NPC cells or normal epithelial cells by cell transfection techniques. Cell Counting Kit-8 (CCK8), Transwell, Enzyme-linked immunosorbent assay (ELISA) apoptosis, and western blotting were adopted to determine the changes in cell activity, invasiveness, and apoptosis after differential miRNA and target gene overexpression or downregulation. Differential analysis of miRNA dataset showed that the expression of miR-26b was significantly downregulated in NPC, in agreement with the validation results of nasopharyngeal carcinoma cell lines. And downregulation of miR-26b expression in normal nasopharyngeal epithelial cells transformed the cells to tumors. CEP135 was identified as the miR-26b downstream target gene by mRNA dataset analysis, and a luciferase reporter test revealed a direct targeting link between the two. Upregulation of CEP135 levels in nasopharyngeal cancer cell lines increased cell activity, accelerated cell migration, and inhibited apoptosis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that CEP135 exerted the above effects on cells via the NF-κB pathway, and co-culture with NF-κB pathway blockers reversed cell biological behavior to the level of the control group. MiR-26b downregulation leads to CEP135 overexpression and NF-κB pathway activation in NPC, which enhances proliferation, migration, and prevents apoptosis of nasopharyngeal carcinoma cells. Therefore, the study further clarifies the biological behavior mechanism of NPC and suggests new therapeutic options for NPC.

Dataset Information

High expression of Fibronectin 1 suppresses apoptosis through the NF-?B pathway and is associated with migration in nasopharyngeal carcinoma.

Publications

High expression of Fibronectin 1 suppresses apoptosis through the NF-κB pathway and is associated with migration in nasopharyngeal carcinoma.

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