Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

This monthly, peer-reviewed journal includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.

Molecular Medicine Reports

Atherosclerosis (AS) is an inflammatory disease linked to endothelial dysfunction. Melatonin is reported to possess substantial anti-inflammatory properties, which has proven to be effective in AS. Emerging literature suggests that pyroptosis plays a critical role during AS progression. However, whether pyroptosis contributes to endothelial dysfunction and the underlying molecular mechanisms remained unexploited. This study was designed to investigate the anti-pyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms. In this study, high fat diet (HFD) treated ApoE(-/-) mice were used as an atherosclerotic animal model. We found intragastric administration of melatonin for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, melatonin also attenuated the expression of pyroptosis-related genes, including NLRP3, ASC, cleaved-caspase1, NF-κB/GSDMD, GSDMD-N termini, IL-1β, and IL-18 in aortic endothelium of melatonin-treated animals. Consistent anti-pyroptotic effects were also observed in ox-LDL-treated human aortic endothelial cells (HAECs). We found that lncRNA MEG3 enhanced pyroptosis in HAECs. Moreover, MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR-223 and to increase NLRP3 expression and enhance endothelial cell pyroptosis. Furthermore, knockdown of miR-223 blocked the anti-pyroptotic actions of melatonin in ox-LDL-treated HAECs. Together, our results suggest that melatonin prevents endothelial cell pyroptosis via MEG3/miR-223/NLRP3 axis in atherosclerosis and therefore melatonin replacement might be considered a new strategy for protecting endothelium against pyroptosis thereby for the treatment of atherosclerosis associated with pyroptosis. This article is protected by copyright. All rights reserved.

Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR-223/NLRP3 axis.

Massive high-throughput sequencing techniques allowed the identification of thousands of noncoding RNAs (ncRNAs) and a plethora of different mRNA processing events occurring in higher organisms. Long ncRNAs can act directly as long transcripts or can be processed into active small si/miRNAs. They can modulate mRNA cleavage, translational repression or the epigenetic landscape of their target genes. Recently, certain long ncRNAs have been shown to play a crucial role in the regulation of alternative splicing in response to several stimuli or during disease. In this review, we focus on recent discoveries linking gene regulation by alternative splicing and its modulation by long and small ncRNAs.

Splicing regulation by long noncoding RNAs

According to recent studies, long non-coding RNA X-inactive specific transcript (XIST) is involved in the development and progression of many malignant tumors including pancreatic cancer. We validated the detailed role of XIST in human pancreatic cancer (PC) cell lines and PC tissues so as to determine its exact function and the mechanism by which it affected PC proliferation. In our research, lncRNA-XIST was specifically upregulated in PC tissues and cell lines, and high XIST expression in PC was related to poorer prognosis (larger tumor size, perineural invasion, lymph node micrometastases, and shorter overall survival). XIST augmented PC cell proliferation. Recently, the interaction between lncRNA and miRNA has been frequently reported to play major role in several biological processes. In the present study, XIST and miR-133a reciprocally inhibited each other in PC cells. Exogenous miR-133a expression significantly inhibited PC cell proliferation. Moreover, as exhibited by luciferase reporter gene assays, miR-133a bound to XIST and the 3'UTR of EGFR by direct targeting. In PC tissues, miR-133a expression was down-regulated and EGFR expression was up-regulated; miR-133a was inversely correlated with EGFR and XIST, respectively; XIST was positively correlated with EGFR. Taken together, these findings will shed light on the role and mechanism of XIST/miR-133a/EGFR in regulating PC cells proliferation. XIST may serve as a potential therapeutic target in PC in the future. J. Cell. Biochem. 118: 3349-3358, 2017. © 2017 Wiley Periodicals, Inc.

LncRNA XIST Promotes Pancreatic Cancer Proliferation Through miR-133a/EGFR.

Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p.

Andrographolide (Andro) has been reported to have anticancer activity in multiple types of cancer due to its capacity to inactivate NF-κB pathway. Previous studies showed the therapeutic potential of targeting NF-κB pathway in nasopharyngeal carcinoma (NPC). However, the anticancer activity of Andro in NPC has not been reported. In this study, we defined the anticancer effects of Andro in NPC and elucidated its potential mechanisms of action. Our results showed that Andro significantly inhibited the proliferation and invasion of NPC cells (P < 0.05, resp.). These anticancer activities were associated with cell apoptosis, cell death and induction of cell cycle arrest, and the downregulation of NF-κB target genes. This work provides evidence that NF-κB pathway is a potential therapeutic target and may also be indispensable in the Andro-mediated anticancer activities in nasopharyngeal carcinoma.

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Andrographolide suppresses proliferation of nasopharyngeal carcinoma cells via attenuating NF-κB pathway.

The present study was designed to investigate the effects of high‑mobility group box 1 (HMGB1) knockdown on the proliferation, migration and invasion of the HONE‑1 human nasopharyngeal carcinoma cell line and explore the possible underlying mechanisms. HMGB1-knockdown HONE‑1 cells were generated by lentiviral transfection, and HMGB1 expression was demonstrated to be obviously decreased in these cells. A Cell Counting kit‑8 assay was used to determine cell proliferation, while flow cytometric analysis was employed to determine the apoptotic rate. In addition, in vitro wound healing, cell adhesion and invasion assays were performed to evaluate the metastatic potential of the cells. Western blot analysis was used to determine the protein expression of apoptosis signaling proteins caspase‑3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, receptor for advanced glycation end products (RAGE) as well as phosphorylated and total extracellular signal-regulated kinase 1/2 in HONE‑1 cells. The results of the present study demonstrated that HMGB1 knockdown suppressed the proliferation, migration and invasion of HONE‑1 cells, the mechanisms of which may be associated with the induction of mitochondria‑mediated apoptosis and inhibition of HMGB1/RAGE pathways.

/pdf/effects-of-high-mobility-group-box-1-knockdown-on-g7jwf66wcc.pdf

Effects of high‑mobility group box 1 knockdown on proliferation, migration and invasion of the HONE‑1 human nasopharyngeal carcinoma cell line

Purpose Apo-E, a secreted protein, is closely related to the migration and invasion of tumor cells. In this study, we aimed to analyze the expression of Apo-E in nasopharyngeal carcinoma (NPC) patients and cell lines, as well as its effects on NPC cell behavior. Patients and methods Our study included 35 patients with NPC from Zhongnan Hospital. Expression levels of Apo-E in patients with NPC were examined by quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemical (IHC) staining. Receiver operating characteristic (ROC) curves were analyzed using the SPSS 22 software to estimate the sensitivity and specificity of the Apo-E protein in diagnosing NPC. Additionally, the level of Apo-E in NPC cell lines (NP69, 6-10B, and 5-8F) was investigated by Western blotting and IHC. Results Levels of Apo-E were higher in NPC patients than in controls. Moreover, ROC analysis revealed that increased Apo-E in the serum of NPC patients may act as a potential biomarker for NPC diagnosis (Area under the curve 0.917). Furthermore, similar results were also identified in NPC cancer cell lines. RNA interference technology was used to overexpress the endogenous Apo-E in the NPC cell line 6-10B. Wound healing and transwell assays indicated that the overexpression of Apo-E increased the number of cell colonies and migration ability, respectively. Conclusion In this study, we found that Apo-E was elevated in NPC patients and may act as a potential biomarker for NPC diagnosis. In addition, Apo-E was upregulated in NPC cell lines and promoted cell growth, migration, and invasion.

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Identification of Apolipoprotein E as a Potential Diagnostic Biomarker of Nasopharyngeal Carcinoma.

Background There is no effective prognostic signature that could predict the prognosis of nasopharyngeal carcinoma (NPC). Methods We constructed a prognostic signature based on five microRNAs using random forest and Least Absolute Shrinkage And Selection Operator (LASSO) algorithm on the GSE32960 cohort (N = 213). We verified its prognostic value using three independent external validation cohorts (GSE36682, N = 62; GSE70970, N = 246; and TCGA-HNSC, N = 523). Through principal component analysis, receiver operating characteristic curve analysis, and C-index calculation, we confirmed the predictive accuracy of this prognostic signature. Results We calculated the risk score based on the LASSO algorithm and divided the patients into high- and low-risk groups according to the calculated optimal cutoff value. The patients in the high-risk group tended to have a worse prognosis outcome and chemotherapy response. The time-dependent receiver operating characteristic curve showed that the 1-year overall survival rate of the five-microRNA signature had an area under the curve of more than 0.83. A functional annotation analysis of the five-microRNA signature showed that the patients in the high-risk group were usually accompanied by activation of DNA repair and MYC-target pathways, while the patients in the low-risk group had higher immune-related pathway signals. Conclusions We constructed a five-microRNA prognostic signature, which could accurately predict the prognosis of nasopharyngeal carcinoma, and constructed a nomogram that could conveniently predict the overall survival of patients.

/pdf/a-five-microrna-signature-predicts-the-prognosis-in-17sh9m1669.pdf

Cen Zhang

Papers

Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p.

Andrographolide suppresses proliferation of nasopharyngeal carcinoma cells via attenuating NF-κB pathway.

Effects of high‑mobility group box 1 knockdown on proliferation, migration and invasion of the HONE‑1 human nasopharyngeal carcinoma cell line

Identification of Apolipoprotein E as a Potential Diagnostic Biomarker of Nasopharyngeal Carcinoma.

A Five-MicroRNA Signature Predicts the Prognosis in Nasopharyngeal Carcinoma.