ABSTRACT
An emerging body of evidence has promoted the understanding of the role of microRNAs (miRNAs) in tumorigenesis and progression, but the mediating function of miRNAs in nasopharyngeal carcinoma (NPC) development remains poorly elucidated. In this study, miR-449b-3p was downregulated in NPC specimens (P < .001) and cells (P < .05). Cytological and animal experiments provided evidence that miR-449b-3p inhibited NPC metastasis in vitro and in vivo. Disintegrin and metalloproteinase 17 (ADAM17) was revealed as a direct target of miR-449b-3p. Rescue experiments suggested that the downregulation of ADAM17 in the miR-449b-3p knockdown cells partially reversed the inhibition of cell invasion and migration. Luciferase reporter assay, chromatin immunoprecipitation assay, and Western blot analysis showed that ADAM17 could suppress the promoter activity and expression of miR-449b-3p by inducing NF-κB transcriptional activity. In conclusion, our study provided new insights into the underlying mechanism of the invasion and metastasis of NPC. The novel miR-449b-3p/ADAM17/NF-κB feedback loop could be a target for the clinical treatment of NPC.
Subject(s)
ADAM17 Protein/metabolism , MicroRNAs/metabolism , NF-kappa B/metabolism , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Neoplasms/metabolism , Animals , Cell Line , Cell Movement , Humans , Male , Mice, Nude , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathologyABSTRACT
BACKGROUND/AIMS: A recent study found that dysregulated microRNA-184 (miR-184) is involved in the proliferation and survival of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the detailed mechanisms of invasion, migration and metastasis of NPC cells. METHODS: Quantitative reverse-transcription PCR (qRT-PCR) and Western blot were used to confirm the expression levels of miR-184 and Notch2. NPC cell invasion and migration were subsequently examined using in vitro cell invasion and wound-healing assays, respectively. MicroRNA (miRNA) target gene prediction databases and dual-luciferase reporter assay were adopted to validate the target genes of miR-184. RESULTS: MiR-184 was downregulated in the NPC cell lines. The miR-184 inhibitor increased the number of invading NPC cells, whereas miR-184 mimics inhibited the invasive ability of such cells. The protein level of E-cadherin decreased, whereas those of N-cadherin and vimentin increased in the anti-miR-184 group. This result showed that miR-184 inhibited NPC cell invasion and metastasis by regulating EMT progression. MiRNA target gene prediction databases indicated the potential of Notch2 as a direct target gene of miR-184. Such a notion was then validated by results of dual-luciferase reporter assay. Notably, shRNANotch2 restrained the EMT and partially abrogated the inhibitory effects of miR-184 on EMT progression in NPC cells. CONCLUSION: MiR-184 functions as a tumour-suppressive miRNA targeting Notch2 and inhibits the invasion, migration and metastasis of NPC.
Subject(s)
Carcinoma/pathology , MicroRNAs/metabolism , Nasopharyngeal Neoplasms/pathology , Receptor, Notch2/metabolism , 3' Untranslated Regions , Animals , Antagomirs/metabolism , Cadherins/metabolism , Carcinoma/metabolism , Cell Line, Tumor , Cell Movement , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/metabolism , Neoplasm Invasiveness , RNA Interference , RNA, Small Interfering/metabolism , Receptor, Notch2/antagonists & inhibitors , Receptor, Notch2/genetics , Vimentin/metabolismABSTRACT
Transforming growth factor beta (TGF-?), a pleiotropic cytokine, promotes cell proliferation and migration in multiple cancers, including nasopharyngeal carcinoma (NPC). microRNA-124 (miR-124) becomes downregulated in NPC and inhibits the tumorigenesis of this disease. However, the role of miR-124 in TGF-?-induced NPC development remains unknown. In this study, constant TGF-? stimulation repressed miR-124 expression, whereas miR-124 overexpression antagonized TGF-?-promoted NPC cell growth and migration. miR-124 overexpression decreased p-SMAD2/3, SMAD4, and p-ERK levels, indicating that ectopic miR-124 overexpression inhibited SMAD and non-SMAD pathways. Pro-oncogenic lncRNA MALAT1 was targeted by miR-124 that regulated ERK/MAPK by targeting MALAT1 independent of the SMAD signaling pathway. In conclusion, our work clarified the significant role of miR-124 in TGF-? signaling pathways independent of the SMAD signaling pathway and showed the potential of miR-124 as a new therapeutic target against NPC.
Subject(s)
Carcinoma/pathology , MicroRNAs/genetics , Nasopharyngeal Neoplasms/pathology , RNA, Long Noncoding/genetics , Transforming Growth Factor beta/metabolism , Carcinoma/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Signaling System/genetics , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Signal Transduction/genetics , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Smad4 Protein/metabolismABSTRACT
Extranodal NK/T-cell lymphoma is closely associated with Epstein-Barr virus (EBV) infection. However, the prognostic value of EBV-DNA in extranodal NK/T-cell lymphoma remains unclear. Thus, we conducted a meta-analysis to estimate its prognostic significance. PubMed, EMBASE, and Web of Science were used to search for studies conducted until June 12, 2017. The pooled hazard ratio (HR) and its 95% confidence interval (CI) were calculated to evaluate the prognostic value of pretreatment EBV-DNA on the overall survival of extranodal NK/T-cell lymphoma. Seven eligible studies on 356 patients with extranodal NK/T-cell lymphoma were pooled for this meta-analysis. Results suggested that the pretreatment EBV-DNA positivity was significantly correlated with the overall survival of extranodal NK/T-cell lymphoma (pooled HR =3.78, 95% CI: 1.52-9.40, p=0.004; heterogeneity test: I2=52%, p=0.05). Subgroup analyses stratified by sample type, survival analysis mode, and HR origin showed that patients with positive pretreatment EBV-DNA had poorer prognosis than those with negative pretreatment EBV-DNA. Moreover, the cut-off value (HR =1.66; 95% CI: 0.73-3.73; p=0.22) might account for the heterogeneity. No significant publication bias was observed. Pretreatment EBV-DNA positivity can predict poor prognosis for patients with extranodal NK/T-cell lymphoma. Future large-scale studies based on prognostic significance of EBV-DNA for patients with extranodal NK/T-cell lymphoma are necessary.
ABSTRACT
Long non-coding RNAs (lncRNAs) have been reported to perform significant roles in cancer development and progression. Our research has found that a novel lncRNA n326322 was higher in nasopharyngeal carcinoma (NPC) cells. Moreover, the gain and loss of functional approaches revealed that the overexpression of lncRNA-n326322 promoted NPC cell proliferation and invasion, whereas the downregulation of lncRNA-n326322 suppressed cell proliferation and invasion. Further experiments demonstrated that potential mechanism may be associated with the activation of PI3K/AKT and ERK/MAPK pathways. Taken together, these results indicate that lncRNA-n326322 is associated with tumorigenesis of NPC.
