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Background: Noncoding RNAs play pivotal roles in the process of autoimmune diseases. However, the definite contributions of these molecules to Behçet's disease (BD) are still unknown. This study aimed to explore the clinical value of a novel competing endogenous (ce) RNA network in the pathogenesis of BD and to assess its use in primary diagnosis. Methods: Bioinformatic analysis was applied to construct a BD-related ceRNA network: lncRNA (MIAT and PVT1)-miRNA (miR-93-5p and miR-124-3p)-mRNA (SOD-2 and MICA). Blood was obtained from 70 BD patients and 30 healthy subjects, and the serum expression of the tested RNAs was estimated via quantitative real-time PCR (qPCR). Serum tumor necrosis factor-alpha (TNF-α) levels were also determined. The associations between these RNAs were further analyzed, and receiver operating characteristic (ROC) curve and logistic regression analyses were employed to validate their diagnostic and prognostic values. Results: The expression levels of the lncRNAs PVT1 and miR-93-5p were significantly increased, whereas those of the lncRNAs MIAT and miR-124-3p, as well as those of the SOD-2 and MICA mRNAs, were significantly decreased in BD patients compared with controls. BD patients had significantly higher serum TNF-α levels than controls did. ROC curve analysis indicated that the selected RNAs could be candidate diagnostic biomarkers for BD. Moreover, the highest diagnostic efficiency was achieved with the combination of MIAT and miR-93-5p or PVT1 and miR-124-3p with either SOD-2 or MICA. Logistic regression analysis revealed that all RNA expression levels could be predictors for BD. Conclusion: Mechanistically, our research revealed a novel ceRNA network that is significantly disrupted in BD. The findings reported herein, highlight the noncoding RNA-molecular pathways underlying BD and identify potential targets for therapeutic intervention. These insights will likely be applicable for developing new strategies for the early diagnosis, management and risk assessment of BD as well as the design of novel preventive measures. Trial registration The protocol for the clinical studies was approved by Cairo University's Faculty of Pharmacy's Research Ethics Committee (approval number: BC 3590) [ABSTRACT FROM AUTHOR]

Oral submucous fibrosis (OSF) is a precancerous condition in the oral cavity, which is closely related to the myofibroblast conversion of buccal mucosal fibroblasts (BMFs) after chronic consumption of areca nut. Emerging evidence suggests pyroptosis, a form of programmed cell death that is mediated by inflammasome, is implicated in persistent myofibroblast activation and fibrosis. Besides, numerous studies have demonstrated the effects of non‐coding RNAs on pyroptosis and myofibroblast activities. Herein, we aimed to target key long non‐coding RNA PVT1 with natural compound, carvacrol, to alleviate pyroptosis and myofibroblast activation in OSF. We first identified PVT1 was downregulated in the carvacrol‐treated fBMFs and then demonstrated that myofibroblast features and expression of pyroptosis makers were all reduced in response to carvacrol treatment. Subsequently, we analysed the expression of PVT1 and found that PVT1 was aberrantly upregulated in OSF specimens and positively correlated with several fibrosis markers. After revealing the suppressive effects of carvacrol on myofibroblast characterisitcs and pyroptosis were mediated by repression of PVT1, we then explored the potential mechanisms. Our data showed that PVT1 may serve as a sponge of microRNA(miR)‐20a to mitigate the myofibroblast activation and pyroptosis. Altogether, these findings indicated that the anti‐fibrosis effects of carvacrol merit consideration and may be due to the attenuation of pyroptosis and myofibroblast activation by targeting the PVT1/miR‐20a axis. [ABSTRACT FROM AUTHOR]

Abstract Background Improper expression of long noncoding RNAs (lncRNAs) can cause various cancers. Single nucleotide polymorphisms (SNPs) affect the expression and function of several key lncRNAs. We assessed the associations of MEG3, PVT1, and H19 lncRNA polymorphisms with susceptibility to gastric cancer (GC). Methods In Ardabil (a high-risk area in North‒West Iran), 795 blood samples were collected from 396 cases and 399 controls. The control subjects were randomly selected from individuals receiving regular physical examinations in this hospital with no self-reported cancer history and were frequency-matched to the case group by sex and 5-year age intervals. All the samples were genotyped via the Infinium HTS platform, which was subsequently followed by rigorous data quality control, as well as statistical and bioinformatic analyses. Results The H19 rs2107425 SNP was associated with GC risk in a recessive model of inheritance (TT vs. CC + CT: OR = 1.87). The PVT1 rs13255292 variant in the overdominant model significantly reduced GC risk (CT vs. CC + TT: OR = 0.74). There was no significant association between H19 rs2839698, MEG3 rs116907618, or rs11160608, or PVT1 rs7017386, rs13254990 tagSNPs and susceptibility to GC. The interaction between H19 rs2107425 TT and PVT1 rs7017386 TC increased GC risk (OR = 3.73; pbon

Abstract Background Noncoding RNAs play pivotal roles in the process of autoimmune diseases. However, the definite contributions of these molecules to Behçet’s disease (BD) are still unknown. This study aimed to explore the clinical value of a novel competing endogenous (ce) RNA network in the pathogenesis of BD and to assess its use in primary diagnosis. Methods Bioinformatic analysis was applied to construct a BD-related ceRNA network: lncRNA (MIAT and PVT1)-miRNA (miR-93-5p and miR-124-3p)-mRNA (SOD-2 and MICA). Blood was obtained from 70 BD patients and 30 healthy subjects, and the serum expression of the tested RNAs was estimated via quantitative real-time PCR (qPCR). Serum tumor necrosis factor-alpha (TNF-α) levels were also determined. The associations between these RNAs were further analyzed, and receiver operating characteristic (ROC) curve and logistic regression analyses were employed to validate their diagnostic and prognostic values. Results The expression levels of the lncRNAs PVT1 and miR-93-5p were significantly increased, whereas those of the lncRNAs MIAT and miR-124-3p, as well as those of the SOD-2 and MICA mRNAs, were significantly decreased in BD patients compared with controls. BD patients had significantly higher serum TNF-α levels than controls did. ROC curve analysis indicated that the selected RNAs could be candidate diagnostic biomarkers for BD. Moreover, the highest diagnostic efficiency was achieved with the combination of MIAT and miR-93-5p or PVT1 and miR-124-3p with either SOD-2 or MICA. Logistic regression analysis revealed that all RNA expression levels could be predictors for BD. Conclusion Mechanistically, our research revealed a novel ceRNA network that is significantly disrupted in BD. The findings reported herein, highlight the noncoding RNA-molecular pathways underlying BD and identify potential targets for therapeutic intervention. These insights will likely be applicable for developing new strategies for the early diagnosis, management and risk assessment of BD as well as the design of novel preventive measures. Trial registration The protocol for the clinical studies was approved by Cairo University’s Faculty of Pharmacy’s Research Ethics Committee (approval number: BC 3590)

Super-enhancers are unique gene expression regulators widely involved in cancer development. Spread over large DNA segments, they tend to be found next to oncogenes. The super-enhancer c-MYC locus forms long-range chromatin looping with nearby genes, which brings the enhancer and the genes into proximity, to promote gene activation. The colon cancer-associated transcript 1 (CCAT1) gene, which is part of the MYC locus, transcribes a lncRNA that is overexpressed in colon cancer cells through activation by MYC. Comparing different types of cancer cell lines using RNA fluorescence in situ hybridization (RNA FISH), we detected very prominent CCAT1 expression in HeLa cells, observed as several large CCAT1 nuclear foci. We found that dozens of CCAT1 transcripts accumulate on the gene locus, in addition to active transcription occurring from the gene. The accumulating transcripts are released from the chromatin during cell division. Examination of CCAT1 lncRNA expression patterns on the single-RNA level showed that unspliced CCAT1 transcripts are released from the gene into the nucleoplasm. Most of these unspliced transcripts were observed in proximity to the active gene but were not associated with nuclear speckles in which unspliced RNAs usually accumulate. At larger distances from the gene, the CCAT1 transcripts appeared spliced, implying that most CCAT1 transcripts undergo post-transcriptional splicing in the zone of the active gene. Finally, we show that unspliced CCAT1 transcripts can be detected in the cytoplasm during splicing inhibition, which suggests that there are several CCAT1 variants, spliced and unspliced, that the cell can recognize as suitable for export. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14–16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that specifically affects preterm infants. Oxygen therapy administered to treat BPD can lead to hyperoxia-induced lung injury, characterized by apoptosis of lung alveolar epithelial cells. Our epitranscriptomic microarray analysis of normal mice lungs and hyperoxia-stimulated mice lungs revealed elevated RNA expression levels of IL-33, as well as increased m6A RNA methylation levels of IL-33 and PVT1 in the hyperoxia-stimulated lungs. This study aimed to investigate the role of the PVT1/IL-33 axis in BPD. A mouse model of BPD was established through hyperoxia induction, and lung histological changes were assessed by hematoxylin–eosin staining. Parameters such as radial alveolar count and mean chord length were measured to assess lung function. Mouse and human lung alveolar epithelial cells (MLE12 and A549, respectively) were stimulated with hyperoxia to create an in vitro BPD model. Cell apoptosis was detected using Western blotting and flow cytometry analysis. Our results demonstrated that silencing PVT1 suppressed apoptosis in MLE12 and A549 cells and improved lung function in hyperoxia-stimulated lungs. Additionally, IL-33 reversed the effects of PVT1 both in vivo and in vitro. Through online bioinformatics analysis and RNA-binding protein immunoprecipitation assays, YTHDC1 was identified as a RNA-binding protein (RBP) for both PVT1 and IL-33. We found that PVT1 positively regulated IL-33 expression by recruiting YTHDC1 to mediate m6A modification of IL-33. In conclusion, silencing PVT1 demonstrated beneficial effects in alleviating BPD by facilitating YTHDC1-mediated m6A modification of IL-33. Inhibition of the PVT1/IL-33 axis to suppress apoptosis in lung alveolar epithelial cells may hold promise as a therapeutic approach for managing hyperoxia-induced lung injury in BPD. [ABSTRACT FROM AUTHOR]

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common type of blood cancer in children. Aberrant expression of long noncoding RNAs (lncRNAs) may set stages for ALL development. LncRNAs are emerging as a novel diagnostic and prognostic biomarker for ALL. Herein, we aimed to evaluate the expression of lncRNA GJA9‐MYCBP and PVT1 in blood samples of ALL and healthy individuals. Methods As a case–control study, 40 pairs of ALL and healthy individual samples were used. The expression of MYC and each candidate lncRNA was measured using quantitative real‐time PCR. Any possible association between the expression of putative noncoding RNAs and clinicopathological characteristics was also evaluated. Results LncRNA GJA9‐MYCBP and PVT1 were significantly upregulated in ALL samples compared with healthy ones. Similarly, mRNA levels of MYC were increased in ALL samples than control ones. Receiver operating characteristic curve analysis indicated a satisfactory diagnostic efficacy (p‐value

Purpose: Pulpitis is a common disease in stomatology, which is caused by dental pulp infection. It was found that long non-coding RNA regulates inflammation and repair responses through competitively sponging microRNAs. This study explored the expression and clinical significance of PVT1 in pulpitis patients, and further investigated the possible regulatory mechanism of PVT1 on pulpitis through in-vitro experiments. Materials and Methods: The expression of PVT1 and miR-128-3p was detected through RT-qPCR. An ROC curve was drawn to estimate the diagnostic significance of PVT1 and miR-128-3p for pulpitis. An in-vitro pulpitis cell model was constructed to evaluate the effects of PVT1 or miR-128-3p on cell proliferation, apoptosis, and inflammatory response. The Luciferase reporter gene explored the interaction between PVT1 and miR-128-3p. Results: The expression of PVT1 increased, while the miR-128-3p level decreased, in the saliva of pulpitis patients. ROC curves showed that both PVT1 and miR-128-3p had the potential to diagnose pulpitis. This in-vitro study revealed that the expression of PVT1 was increased in the pulpitis cell model. A low level of PVT1 suppressed the hDPCs injury induced by LPS. The Luciferase reporter gene verified the targeting relationship between PVT1 and miR-128-3p, and the latter was negatively regulated by PVT1. Further in-vitro studies showed that inhibition of miR-128-3p could reverse the effect of si-PVT1 on cell viability, cell apoptosis and inflammatory response. Conclusion: This study revealed that knockdown of PVT1 may suppress the damage in pulpitis cell models induced by LPS via targeting miR-128-3p. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate the role of plasmacytoma variant translocation 1 (PVT1), a long non‐coding RNA, in glioblastoma multiforme (GBM) and its impact on the tumor microenvironment (TME). Methods: We assessed aberrant PVT1 expression in glioma tissues and its impact on GBM cell growth in vitro and in vivo. Additionally, we investigated PVT1's role in influencing glioma‐associated macrophages. To understand PVT1's role in cell growth and the immunosuppressive TME, we performed a series of comprehensive experiments. Results: PVT1 was overexpressed in GBM due to copy number amplification, correlating with poor prognosis. Elevated PVT1 promoted GBM cell proliferation, while its downregulation inhibited growth in vitro and in vivo. PVT1 inhibited type I interferon‐stimulated genes (ISGs), with STAT1 as the central hub. PVT1 correlated with macrophage enrichment and regulated CX3CL1 expression, promoting recruitment and M2 phenotype polarization of macrophages. PVT1 localized to the cell nucleus and bound to DHX9, enriching at the promoter regions of STAT1 and CX3CL1, modulating ISGs and CX3CL1 expression. Conclusion: PVT1 plays a significant role in GBM, correlating with poor prognosis, promoting cell growth, and shaping an immunosuppressive TME via STAT1 and CX3CL1 regulation. Targeting PVT1 may hold therapeutic promise for GBM patients. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic obstructive pulmonary disease (COPD) is a serious health burden worldwide with high mortality. LncRNA plasmacytoma variant translocation 1 (PVT1) has been illustrated to serve as a biomarker for COPD progression. Nonetheless, its specific functions and mechanisms in COPD are unclarified. Methods Cigarette smoke extract (CSE) was utilized to stimulate 16HBE cells, and cigarette smoke combining with lipopolysaccharide (LPS) was employed to induce COPD in rats. Western blotting and RT-qPCR were utilized for measuring protein and RNA levels. Flow cytometry was implemented for detecting cell apoptosis. Concentrations of inflammatory factors TNF-α and IFN-γ were examined using ELISA. Luciferase reporter assay was utilized for verifying the interaction between molecules. Hematoxylin–eosin staining was performed for histological analysis of rat lung tissues. Results PVT1 was highly expressed in CSE-stimulated 16HBE cells and the lungs of COPD rats. PVT1 depletion restored the viability, restrained apoptosis and hindered inflammatory cytokine production in 16HBE cells under CSE treatment and alleviated pathological damages in COPD rats. PVT1 bound to miR-30b-5p and miR-30b-5p targeted BCL2 like 11 (BCL2L11). Overexpressing BCL2L11 offset the above effects mediated by PVT1 in CSE-triggered 16HBE cells. Conclusion PVT1 enhances apoptosis and inflammation of 16HBE cells under CSE stimulation by modulating miR-30b-5p/BCL2L11 axis.

Objective: All forms of diabetes result from insufficient functional β-cell mass. Thus, achieving the therapeutic goal of expanding β-cell mass requires a better mechanistic understanding of how β-cells proliferate. Glucose is a natural β-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. Methods: Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. Results: We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated β-cell proliferation. Conclusions: The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter.

Background: Acquired drug-resistance is the major risk factor for poor prognosis and short-term survival in patients with osteosarcoma (OS). Accumulating evidence has revealed that long noncoding RNAs (lncRNAs), including plasmacytoma variant translocation 1 (PVT1), play potential regulatory roles in the malignant development of OS. Considering the subcellular distribution of PVT1 as both nuclear and cytoplasmic lncRNA, a thorough exploration of its extensive mechanisms becomes essential. Methods: The GEO database was utilized for the acquisition of gene expression data, which was subsequently analyzed to fulfill the research objectives. The subcellular localization of PVT1 in OS cells was determined using fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the sensitivity of OS cells to doxorubicin was comprehensively evaluated through measurements of cell viability, site-specific proliferation capacity, and the relative expression abundance of multidrug resistance-related proteins (MRPs). In order to investigate the differential response of OS cells with varying levels of PVT1 expression to doxorubicin, pulmonary metastasis mice models were established for in vivo studies. Molecular interactions were further examined using the dual-luciferase assay and RNA immunoprecipitation assay (RIP) to analyze the binding sites of miR-15a-5p and miR-15b-5p on PVT1 and G1/S-specific cyclinD1 (CCND1) mRNA. Furthermore, the chromatin immunoprecipitation (ChIP) and dual-luciferase assay were employed to assess the transcriptional activation of the proto-oncogene c-myc (MYC) on the CCND1 promoter and identify the corresponding binding sites. Results: In doxorubicin resistant OS cells, transcription levels of PVT1, MYC and CCND1 were significantly higher than those in original cells. In vivo experiments demonstrated that OS cells rich in PVT1 expression exhibited enhanced tumorigenicity and resistance to doxorubicin. In vitro experiments, it has been observed that overexpression of PVT1 in OS cells is accompanied by an upregulation of CCND1, thereby facilitating resistance to doxorubicin. Nonetheless, this PVT1-induced resistance can be effectively attenuated by the knockdown of CCND1. Mechanistically, PVT1 functions as a competitive endogenous RNA (ceRNA) that influences the expression of CCND1 by inhibiting the degradation function of miR-15a-5p and miR-15b-5p on CCND1 mRNA. Additionally, as a neighboring gene of MYC, PVT1 plays a role in maintaining MYC protein stability, which further enhances MYC-dependent CCND1 transcriptional activity. Conclusion: The resistance of OS cells to doxorubicin is facilitated by PVT1, which enhances the expression of CCND1 through a dual mechanism. This findings offer a novel perspective for comprehending the intricate regulatory mechanisms of long non-coding RNA in influencing the expression of coding genes.

Background: Chronic obstructive pulmonary disease (COPD) is a serious health burden worldwide with high mortality. LncRNA plasmacytoma variant translocation 1 (PVT1) has been illustrated to serve as a biomarker for COPD progression. Nonetheless, its specific functions and mechanisms in COPD are unclarified. Methods: Cigarette smoke extract (CSE) was utilized to stimulate 16HBE cells, and cigarette smoke combining with lipopolysaccharide (LPS) was employed to induce COPD in rats. Western blotting and RT-qPCR were utilized for measuring protein and RNA levels. Flow cytometry was implemented for detecting cell apoptosis. Concentrations of inflammatory factors TNF-α and IFN-γ were examined using ELISA. Luciferase reporter assay was utilized for verifying the interaction between molecules. Hematoxylin–eosin staining was performed for histological analysis of rat lung tissues. Results: PVT1 was highly expressed in CSE-stimulated 16HBE cells and the lungs of COPD rats. PVT1 depletion restored the viability, restrained apoptosis and hindered inflammatory cytokine production in 16HBE cells under CSE treatment and alleviated pathological damages in COPD rats. PVT1 bound to miR-30b-5p and miR-30b-5p targeted BCL2 like 11 (BCL2L11). Overexpressing BCL2L11 offset the above effects mediated by PVT1 in CSE-triggered 16HBE cells. Conclusion: PVT1 enhances apoptosis and inflammation of 16HBE cells under CSE stimulation by modulating miR-30b-5p/BCL2L11 axis. [ABSTRACT FROM AUTHOR]

The characteristics of ncRNA in children with autism spectrum disorder (ASD) were observed to disclose a theoretical basis for further research on molecular markers for early warning of ASD. Children with ASD and normal control children were recruited to collect peripheral blood RNA samples. The concentration of PVT1 and miR-21-5p was quantitatively analyzed by qRT-PCR. Pearson correlation coefficient method was used to evaluate the link between PVT1 level and miR-21-5p level of the children. Receiver operating characteristic (ROC) curves were applied to reckon the predictive value of PVT1, miR-21-5p, and their combination in ASD. The interconnection of PVT1 with miR-21-5p was represented by luciferase reporter assay. The targeted genes of miR-21-5p were predicted. The enrichment and protein interaction analysis of these genes was carried out to find the important core genes and analyze their value in ASD. In the disease group, the level of PVT1 was downregulated, while the content of miR-21-5p was upregulated. The expression level of serum miR-21-5p was negatively correlated with the level of PVT1. Luciferase reporter gene assay documented that PVT1 directly targeted miR-21-5p. ROC curve showed that PVT1, miR-21-5p, and their combination showed clinical value for disease diagnosis. The functional enrichment analysis showed that the targets of miR-21-5p participated in ASD by regulating related functions and pathways. Reduced expression of PVT1 and raised miR-21-5p were good diagnostic markers for ASD, which would provide a basis for effective prevention, early diagnosis, and early intervention of ASD. [ABSTRACT FROM AUTHOR]

Objective. Our study aims to investigate the long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) in lower extremity arteriosclerosis obliterans (LEASO) patient serum and its clinical significance in LEASO. Patients and Methods. From July 2021 to April 2022, 133 LEASO patients diagnosed at the Qingdao Municipal Hospital were included. Among them, 44 complicated with coronary artery disease (CAD) were classified as the LEASO with CAD group. The remaining 89 were marked as the LEASO group, which was classified into single (nD48) and double (nD41) lower limb groups, with the former being subclassified into the left (nD28) and right (nD20) lower limb groups based on the affected sites. Fifty healthy individuals who came to our hospital for physical examination during the same period were randomly included and defined as the Healthy Control group. PVT1 expression was detected in serum samples from each group using a quantitative reverse transcriptase-polymerase chain reaction, and differences in expression levels were calculated. The ankle-brachial index (ABI) of patients in the LEASO group was measured using a sphygmomanometer, and its correlation with PVT1 was analyzed. Clinical data and laboratory test results (including blood routine, liver and renal function, and blood lipids) were collected for all patients upon admission. Logistic regression analyses were performed to determine the influence of PVT1 and laboratory test results on LEASO. The diagnosis and prediction of LEASO were obtained by combing PVT1 with laboratory test indicators. Results. It was found that lncRNA PVT1 expression was the highest in the serum of the LEASO withCADgroup, followed by the LEASO and control groups (P <0.05). Within the LEASO group, no significant difference in PVT1 expression was seen between the left and right limbs (P > 0.05), nor between the single and double lower limb groups. Furthermore, the PVT1 expression increased with the Rutherford grades, indicating a negative correlation between PVT1 and ABI. Logistic regression analysis revealed that triglycerides (OR D 2.972, 95% CI [1.159≥7.618]), cholesterol (OR D 6.655, 95% CI [1.490≥29.723]), C-reactive protein (OR D 1.686, 95% CI [1.218≥2.335]), and PVT1 (OR D 2.885, 95% CI [1.350≥6.167]) were independent risk factors for LEASO. Finally, strong sensitivity was observed in the receiver operating characteristic curve when combining PVT1 with meaningful laboratory indicators to diagnose and predict LEASO. Conclusion. lncRNA PVT1 promotes LEASO occurrence and progression and is related to atherosclerosis severity. The expression of PVT1 was negatively correlated with ABI. Logistic regression analysis suggested that blood lipid levels and inflammatory reactions might be related to LEASO occurrence. PVT1 was incorporated into laboratory indicators to predict LEASO. The subject's working curve area was large, and the prediction results were highly sensitive. [ABSTRACT FROM AUTHOR]

Abstract Background PVT1, a previously uncharacterized lncRNA, was identified as a critical regulator involved in multiple functions in tumor, including cell proliferation, cell motility, angiogenesis and so on. However, the clinical significance and underlying mechanism of PVT1 was not be fully explored in glioma. Methods In this study, 1210 glioma samples with transcriptome data from three independent databases (CGGA RNA-seq, TCGA RNA-seq and GSE16011 cohorts) were enrolled in this study. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were collected from TCGA cohort. The R software was performed for statistical calculations and graphics. Furthermore, we validated the function of PVT1 in vitro. Results The results indicated that higher PVT1 expression was associated with aggressive progression of glioma. Cases with higher PVT1 expression always accompanied by PTEN and EGFR alteration. In addition, functional analyses and western blot results suggested that PVT1 inhibited the sensitivity of TMZ chemotherapy via JAK/STAT signaling. Meanwhile, knockdown of PVT1 increased the sensitivity of TZM chemotherapy in vitro. Finally, high PVT1 expression was associated with reduced survival time and may serve as a strong prognostic indicator for gliomas. Conclusions This study demonstrated that PVT1 expression strongly correlated with tumor progression and chemo-resistance. PVT1 may become a potential biomarker for the diagnosis and treatment in glioma.

Abstract Background Microvascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown. Methods A ceRNA regulatory network was constructed based on RNA‐seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: “MCC,” “Degree,” “Betweenness,” and “Stress.” Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value. Results The ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR‐1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR‐1258 was an independent predictor for MVI in patients with HCC. Conclusion The PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research.

Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p

Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) has been reported to be a vital modulator in tumorigenesis of gastric cancer (GC). However, the detailed regulatory mechanism of PVT1 in GC remains largely unclear. In this work, the expressions of PVT1 and microRNA-16 (miR-16) were detected by quantitative real-time PCR (qRT-PCR) in GC tissues and cell lines. GC cell lines NCI-N87 and MKN45 cell lines were chosen for the following assays. After PVT1 was overexpressed or depleted, CCK-8 and Transwell assays were performed to examine the cell viability and invasive capacity. Cell cycle was analyzed by flow cytometry. The expression of cyclin D1 (CCND1) at mRNA and protein levels was measured by qRT-PCR and western blot. The competitive endogenous RNA molecular mechanism among PVT1, miR-16 and CCND1 was verified by bioinformatics analysis, luciferase-reporter gene assay and RNA immunoprecipitation assay. In the present study, it was revealed that PVT1 expression was remarkably evaluated in GC tissues and cell lines than that in the corresponding control group. PVT1 positively regulated the proliferation, migration and cell cycle progression of GC cells. Besides, miR-16 was identified as a target of PVT1, and CCND1 was identified as a target of miR-16. The depletion of PVT1 promoted the expression of miR-16 and suppressed CCND1 expression. Moreover, either miR-16 inhibitor or CCND1 overexpression plasmid could reverse the promoting effects of PVT1 on the malignant biological behaviors of GC cells. In conclusion, PVT1 promoted CCND1 expression by negatively regulating miR-16 expression to enhance the viability, invasion and cell cycle progression of GC cells.

Abstract Background All cell types express long non-coding RNAs (lncRNAs), which have the potential to play a role in carcinogenesis by altering the levels of their expression. Squamous cell carcinoma of the esophagus (ESCC) is a deadly disease with a poor prognosis and a high frequency of lymphatic metastases. Understanding the functional role and signaling pathways of two neighboring lncRNAs, CCAT1 and PVT1, in this oncogene’s pathogenesis may help us determine ESCC. Furthermore, it is still unclear whether these lncRNAs are linked to the clinicopathological characteristics of patients with ESCC. Methods For this study, we used biopsy from the Imam Khomeini Cancer Institute’s tumor bank in Tehran, Iran to obtain 40 ESCC tumor samples and their normal margin counterparts. The expression levels of the CCAT1, PVT1, and c-MYC genes were assessed using quantitative Real-Time RT-PCR. Additionally, demographic data and clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node, and metastasis, were taken into consideration. Graphpad prism version 8 was used for bioinformatics analyses. Results Comparing ESCC tissues to non-tumor tissues, we found significant upregulation of PVT1, CCAT1, and c-MYC. Patients with ESCC who had increased PVT1 expression also had higher rates of advanced stage and lymph node metastasis, whereas increased CCAT1 expression was only linked to advanced stage and wasn’t associated with lymph node metastasis. In predicting ESCC, CCAT1 (p

Research has shown that long-chain noncoding RNAs (lncRNAs) are involved in the regulation of a variety of biological processes, including peripheral nerve regeneration, in part by acting as competing endogenous RNAs. c-Jun plays a key role in the repair of peripheral nerve injury. However, the precise underlying mechanism of c-Jun remains unclear. In this study, we performed microarray and bioinformatics analysis of mouse crush-injured sciatic nerves and found that the lncRNA Pvt1 was overexpressed in Schwann cells after peripheral nerve injury. Mechanistic studies revealed that Pvt1 increased c-Jun expression through sponging miRNA-214. We overexpressed Pvt1 in Schwann cells cultured in vitro and found that the proliferation and migration of Schwann cells were enhanced, and overexpression of miRNA-214 counteracted the effects of Pvt1 overexpression on Schwann cell proliferation and migration. We conducted in vivo analyses and injected Schwann cells overexpressing Pvt1 into injured sciatic nerves of mice. Schwann cells overexpressing Pvt1 enhanced the regeneration of injured sciatic nerves following peripheral nerve injury and the locomotor function of mice was improved. Our findings reveal the role of lncRNAs in the repair of peripheral nerve injury and highlight lncRNA Pvt1 as a novel potential treatment target for peripheral nerve injury.

Abstract Background Most susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies (GWAS) are located in non-coding regions, and the mechanism of action remains unclear. The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) on long non-coding RNAs (lncRNAs) that affect competing endogenous RNAs (ceRNA) regulation mechanism with the risk and prognosis of HCC. Methods Based on a set of bioinformatics strategies, eight lncRNA genes that affect HCC through the mechanism of lncRNA-mediated ceRNA were systematically screened, and 15 SNPs that affect microRNA (miRNA) binding in these lncRNA genes were annotated. Genotyping was performed in 800 HCC cases and 801 healthy controls to examine associations of these SNPs with HCC in a northeastern Chinese Han population. Results The GG, GC and GG + GC genotypes of HOTAIR rs7958904 were associated with a 0.65, 0.59 and 0.63-fold decreased HCC risk, respectively. In addition, HCC patients with PVT1 rs3931282 AA + GA genotypes were less prone to develop late-stage cancers in a stratified analysis of clinical characteristics. When stratified by clinical biochemical indexes, rs1134492 and rs10589312 in PVT1 and rs84557 in EGFR-AS1 showed significant associations with aspartate aminotransferase (AST), alanine aminotransferase (ALT) or AST/ALT ratio in HCC patients. Furthermore, we constructed potential ceRNA regulatory axes that might be affected by five positive SNPs to explain the causes of these genetic associations. Conclusions HOTAIR rs7958904, PVT1 rs3931282, rs1134492 and rs10589312, and EGFR-AS1 rs84557 might be predictors for HCC risk or prognosis. Our results provide new insights into how SNPs on lncRNA-mediated ceRNAs confer interindividual differences to occurrence and progression of HCC.

Abstract Background N6-methyladenosine (m6A) is the most common posttranscriptional modification of RNA and plays critical roles in human cancer progression. However, the biological function of m6A methylation requires further studied in cancer, especially in tumor angiogenesis. Methods A public database was used to analyze the expression and overall survival of ALKBH5 and PVT1 in lung cancer patients. CCK-8 and colony formation assays were performed to detect cell proliferation, a transwell assay was used to assess cell migration, and a tube formation assay was performed to assess angiogenic potential in vitro. A zebrafish lung cancer xenograft model was used to verify the function of ALKBH5 and PVT1 in vivo. Western blot assays were used to measure the relative protein expression in lung cancer cells. SRAMP predictor analysis and RNA stability experiments were used to examine the potential m6A modification. Results Bioinformatics analysis showed that the expression levels of m6A-related genes were changed significantly in lung cancer tissues compared with normal lung tissues. We then identified that ALKBH5 was upregulated in lung cancer tissues and associated with poor prognosis of lung cancer patients by analyzing a public database. Knockdown of ALKBH5 inhibited the proliferation and migration of cultured lung cancer cell lines. Zebrafish lung cancer xenografts showed that ALKBH5 silencing also suppressed the growth and metastasis of lung cancer cells. Moreover, knockdown of ALKBH5 inhibited the angiogenesis of lung cancer in vitro and in vivo. Mechanistic studies showed that knockdown of ALKBH5 decreased the expression and stability of PVT1 in lung cancer cells. We next observed that PVT1 promoted the progression of lung cancer cells in vitro and in vivo and regulated the expression of VEGFA and angiogenesis in lung cancer. Finally, rescue experiments revealed that ALKBH5 regulated the proliferation, migration and angiogenesis of lung cancer cells, partially through PVT1. Conclusion Our results demonstrate that ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the expression and stability of PVT1, which provides a potential prognostic and therapeutic target for lung cancer patients.

Abstract Long noncoding RNAs are involved in epigenetic gene modification, including binding to the chromatin rearrangement complex in pre-transcriptional regulation and to gene promoters in gene expression regulation, as well as acting as microRNA sponges to control messenger RNA levels in post-transcriptional regulation. An increasing number of studies have found that long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays an important role in cancer development. In this review of a large number of studies on PVT1, we found that PVT1 is closely related to tumor onset, proliferation, invasion, epithelial–mesenchymal transformation, and apoptosis, as well as poor prognosis and radiotherapy and chemotherapy resistance in some cancers. This review comprehensively describes PVT1 expression in various cancers and presents novel approaches to the diagnosis and treatment of cancer.

Aim: This study is performed to analyze the role of long non‐coding RNA plasmacytoma variant translocation 1 in prostate cancer. Methods and materials: Plasmacytoma variant translocation 1, miR‐515‐5p, and high mobility group B3 mRNA expressions were examined using quantitative real‐time polymerase chain reaction and immunohistochemistry. After gain‐of‐function and loss‐of‐function models were established, the changes in cell proliferation, migration, and invasion were evaluated using cell counting kit‐8 assay, 5‐ethynyl‐2′‐deoxyuridine assay, and Transwell experiments. Validation of the targeting relationships between plasmacytoma variant translocation 1 and miR‐515‐5p, and between miR‐515‐5p and high mobility group B3 was conducted using bioinformatics prediction, a dual‐luciferase reporter assay, and an RNA immunoprecipitation experiment. Moreover, the effects of plasmacytoma variant translocation 1 and miR‐515‐5p on high mobility group B3 protein expression were examined using Western blot. Results: Plasmacytoma variant translocation 1 expression and high mobility group B3 expression were up‐regulated in prostate cancer tissues and cell lines while miR‐515‐5p expression was down‐regulated. Plasmacytoma variant translocation 1 knockdown restrained the proliferation, migration, and invasion of LNCaP and DU145 cells in vitro, and the transfection with miR‐515‐5p inhibitors reversed these effects. Mechanistically, plasmacytoma variant translocation 1 could repress the function of miR‐515; high mobility group B3 was proved to be a target gene of miR‐515‐5p, and its expression could be indirectly positively modulated by plasmacytoma variant translocation 1. Conclusion: Plasmacytoma variant translocation 1 accelerates prostate cancer progression by repressing miR‐515‐5p's function to upregulate high mobility group B3 expression. [ABSTRACT FROM AUTHOR]

Background: Microvascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown. Methods: A ceRNA regulatory network was constructed based on RNA‐seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: "MCC," "Degree," "Betweenness," and "Stress." Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value. Results: The ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR‐1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR‐1258 was an independent predictor for MVI in patients with HCC. Conclusion: The PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research. [ABSTRACT FROM AUTHOR]

Background: Pulpitis is a disease mainly caused by bacterial infection. Long noncoding RNAs (lncRNAs) influence the advancement of pulpitis. In this paper, we reconnoitered the characters of lncRNA plasmacytoma variant translocation 1 (PVT1) in pulpitis. Objective: PVT1, microRNA-30b-5p (miR-30b-5p) and fibrillin 1 (FBN1) levels were identified by qRT-PCR and western blot. In addition, the cell functions were scrutinized. Additionally, the link between miR-30b-5p and PVT1 or FBN1 was identified by dual-luciferase reporter assay. Result: The contents of PVT1 and FBN1 were augmented, but the miR-30b-5p level was declined in pulpitis. Knockdown of PVT1 enhanced cell proliferation and cell vitality, whereas inhibited cell inflammatory reaction in HDPFs under LPS stimulation. In mechanism, PVT1 acted as a miR-30b-5p sponge to adjust the content of FBN1. Moreover, miR-30b-5p mediated LPS-mediated repression of proliferation and promotion of inflammatory reaction HDPFs by FBN1. Conclusion: PVT1 expedited the improvement of pulpitis via miR-30b-5p/FBN1. Article highlights: The expression of PVT1 was upregulated in pulpitis. Silencing PVT1 enhanced cell proliferation and cell vitality, whereas inhibited cell inflammatory reaction in HDPFs. PVT1 expedited pulpitis via miR-30b-5p. MiR-30b-5p impeded pulpitis by targeting FBN1. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic foot ulcer (DFU), persistent hyperglycemia and inflammation, together with impaired nutrient and oxygen deficiency, can present abnormal angiogenesis following tissue injury such that these tissues fail to heal properly. It is critical to design a new treatment method for DFU patients with a distinct biomechanism that is more effective than current treatment regimens. Method Graphene oxide (GO) was combined with a biocompatible polymer as a kind of modified GO-based hydrogel. The characterization of our biomaterial was measured in vitro. The repair efficiency of the biomaterial was evaluated in the mouse full-skin defect models. The key axis related to diabetic wound (DW) was identified and investigated using bioinformatics analyses and practical experiments. Result In the study, we found that our modified GO-based wound dressing material is a promising option for diabetic wound. Secondly, our biomaterial could enhance the secretion of small EVs (sEVs) with more miR-21 by adipose-derived mesenchymal stem cells (AD-MSCs). Thirdly, the PVT1/PTEN/IL-17 axis was found to be decreased to promote DFU wound healing by modifying miR-21 with the discovery of PVT1 as a critical LncRNA by bioinformatics analysis and tests. Conclusion These findings could aid in the development of clinical care strategies for DFU wounds.

Background: All cell types express long non-coding RNAs (lncRNAs), which have the potential to play a role in carcinogenesis by altering the levels of their expression. Squamous cell carcinoma of the esophagus (ESCC) is a deadly disease with a poor prognosis and a high frequency of lymphatic metastases. Understanding the functional role and signaling pathways of two neighboring lncRNAs, CCAT1 and PVT1, in this oncogene's pathogenesis may help us determine ESCC. Furthermore, it is still unclear whether these lncRNAs are linked to the clinicopathological characteristics of patients with ESCC. Methods: For this study, we used biopsy from the Imam Khomeini Cancer Institute's tumor bank in Tehran, Iran to obtain 40 ESCC tumor samples and their normal margin counterparts. The expression levels of the CCAT1, PVT1, and c-MYC genes were assessed using quantitative Real-Time RT-PCR. Additionally, demographic data and clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node, and metastasis, were taken into consideration. Graphpad prism version 8 was used for bioinformatics analyses. Results: Comparing ESCC tissues to non-tumor tissues, we found significant upregulation of PVT1, CCAT1, and c-MYC. Patients with ESCC who had increased PVT1 expression also had higher rates of advanced stage and lymph node metastasis, whereas increased CCAT1 expression was only linked to advanced stage and wasn't associated with lymph node metastasis. In predicting ESCC, CCAT1 (p < 0.05) was found to be an important factor. Overall survival was reduced by c-MYC and PVT1 overexpression (p < 0.001), according to Kaplan-Meier analysis. PVT1, CCAT1, and c-MYC were found to interact with 23 miRNAs with high and medium score classes, as shown in a bioinformatics study. We summarized the experimentally proven interactions between c-MYC, PVT1, and CCAT1 and other miRNAs, lncRNAs, and proteins. Conclusion: This is the first report that CCAT1, PVT1 and c-MYC have been found to be up-regulated simultaneously in ESCC. It is possible that these genes may be involved in ESCC as a result of these findings. Therefore, as consequence, more research is needed to determine whether or not these lncRNAs play an oncogenic role in ESCC development and progression, as well as the regulatory mechanisms that control them. [ABSTRACT FROM AUTHOR]

Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) has been reported to be a vital modulator in tumorigenesis of gastric cancer (GC). However, the detailed regulatory mechanism of PVT1 in GC remains largely unclear. In this work, the expressions of PVT1 and microRNA-16 (miR-16) were detected by quantitative real-time PCR (qRT-PCR) in GC tissues and cell lines. GC cell lines NCI-N87 and MKN45 cell lines were chosen for the following assays. After PVT1 was overexpressed or depleted, CCK-8 and Transwell assays were performed to examine the cell viability and invasive capacity. Cell cycle was analyzed by flow cytometry. The expression of cyclin D1 (CCND1) at mRNA and protein levels was measured by qRT-PCR and western blot. The competitive endogenous RNA molecular mechanism among PVT1, miR-16 and CCND1 was verified by bioinformatics analysis, luciferase-reporter gene assay and RNA immunoprecipitation assay. In the present study, it was revealed that PVT1 expression was remarkably evaluated in GC tissues and cell lines than that in the corresponding control group. PVT1 positively regulated the proliferation, migration and cell cycle progression of GC cells. Besides, miR-16 was identified as a target of PVT1, and CCND1 was identified as a target of miR-16. The depletion of PVT1 promoted the expression of miR-16 and suppressed CCND1 expression. Moreover, either miR-16 inhibitor or CCND1 overexpression plasmid could reverse the promoting effects of PVT1 on the malignant biological behaviors of GC cells. In conclusion, PVT1 promoted CCND1 expression by negatively regulating miR-16 expression to enhance the viability, invasion and cell cycle progression of GC cells. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the serum plasmacytoma variant translocation 1 (PVT1) level in pregnant women with gestational hypertension and pre-eclampsia and its diagnostic value for diseases and its influence on pregnancy outcome. Serum PVT1 levels in 72 pregnant women with gestational hypertension, 72 pregnant women with pre-eclampsia and 71 healthy pregnant women were evaluated by RT-qPCR, and the diagnostic significance of PVT1 for gestational hypertension was verified by receiver operator characteristic (ROC) curve. The correlation between PVT1 and clinical indicators were evaluated by Pearson correlation coefficient method. Logistic regression analysis evaluated the influencing factors in the development process of gestational hypertension to pre-eclampsia. The effect of PVT1 level on pregnancy outcome was evaluated by prognostic analysis. Results showed that PVT1 level was down-regulated in gestational hypertension group compared with healthy control group, whereas PVT1 level was downregulated more significantly in pre-eclampsia group than in gestational hypertension group. ROC curve showed that PVT1 had high diagnostic accuracy for gestational hypertension. Pearson correlation coefficient and multiple linear regression analysis showed that PVT1 was correlated with systolic blood pressure, diastolic blood pressure, interleukin (IL)-6 and tumor necrosis factor-α. Logistic regression analysis revealed that IL-6 and PVT1 were the influencing factors of gestational hypertension to pre-eclampsia transition. Moreover, prognostic analysis manifested that the incidence of fetal growth restriction in low PVT1 expression group was significantly higher than that in high PVT1 expression group. The expression level of PVT1 has a high diagnostic accuracy for gestational hypertension, and the low PVT1 expression group is more prone to fetal growth restriction. [ABSTRACT FROM AUTHOR]

Introduction: Vascular smooth muscle cells (VSMC) switched from a contractile phenotype to a synthetic phenotype during the decidual spiral artery (SPAs) remodeling process. The lncRNA plasmacytoma variant translocation 1 (PVT1) and glucose metabolism have been found to regulate the VSMC phenotype switch. This study aimed to analyze the dynamic expression of PVT1 and glycolytic key enzymes hexokinase2 (HK2) at different remodeling stages in early human pregnancy and elucidate the underlying mechanism of the PVT1/miR-145-5p/HK2 axis involved in the spiral artery remodeling.Methods: qRT-PCR, Western blot (WB) analysis, Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect the expression and localization of PVT1 and HK2 in decidual tissue. HA-VSMCs were transfected with specific siRNA, shRNA and plasmids to regulate corresponding genes. Extracellular lactate, cellular ATP, ROS, and intracellular NADPH levels were measured using the corresponding assay kits. Migration was measured by wound-healing and Transwell assays. Contractile phenotypic markers α-SMA, MYH11 with calponin and synthetic phenotypic markers OPN and vimentin were detected by WB. The PDC model was used to detect the degree of spiral arterial remodeling.Results: PVT1 and HK2 were upregulated with gestational age (GA) increasing in decidual tissue during the early pregnancy. HK2 regulated the glycolytic activity and VSMC phenotype switch in vitro. PVT1 regulated the glycolytic activity and VSMC phenotype switch through HK2. PVT1 played a ceRNA role in regulating HK2 expression by sponging miR-145-5p. PVT1 and HK2 influenced spiral artery remodeling in the PDC model.Discussion: PVT1 and HK2 were upregulated, and miR-145-5p was downregulated in decidua with the GA increasing. Meanwhile, the PVT1/miR-145-5p/HK2 axis may be involved in regulating the phenotypic switch and migratory capacity of VSMCs by affecting glycolysis in decidual SPAs remodeling. [ABSTRACT FROM AUTHOR]

LncRNA PVT1 has been implicated in numerous pathophysiological processes and diseases, especially cancers. However, the role and mechanism of PVT1 in the tumorigenesis of glioblastoma remain unclear. We investigated the alteration of PVT1 and its key functions in glioblastoma. PVT1 was upregulated and associated with poor prognosis in glioblastoma. We demonstrated that PVT1 silencing suppressed cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistic investigations found that PVT1 interacted with TRIM24 directly and increased its protein stability. PVT1 recruited COPS5 to deubiquitinate TRIM24; reciprocally, PVT1 depletion impaired the interaction between COPS5 and TRIM24, resulting in decreased expression of TRIM24. PVT1, TRIM24, and COPS5 coordinately contributed to the activation of STAT3 signaling and malignant phenotype of glioblastoma. Collectively, this study elucidates the essential role of PVT1 in the tumorigenesis of glioblastoma, which provides candidacy therapeutic target for glioblastoma treatment.

• We performed in-depth single-cell RNA sequencing and ATAC-seq in SCCM and control patients. • We identified six cell types in the SCCM and control vessels and found that the proportion of both the endothelial and smooth muscle cells were decreased in SCCM conditions while immune cells showed higher proportion in SCCM conditions than that in control conditions. • Among the four overlapped genes selected from pseudo-time analysis, we found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. • NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 exhibited significantly elevated expression in SCCM blood vessels comparing with the control vessels. Cerebral cavernous malformation (CCM) is a low-flow, bleeding-prone vascular disease that can cause cerebral hemorrhage, seizure and neurological deficits. Its inheritance mode includes sporadic or autosomal dominant inheritance with incomplete penetrance, namely sporadic CCM (SCCM) and familial CCM. SCCM is featured by single lesion and single affection in a family. Among CCM patients especially SCCM, the pathogenesis of the corresponding phenotypes and pathological features or candidate genes have not been fully elucidated yet. Here, we performed in-depth single-cell RNA sequencing (scRNA-Seq) and bulk assay for transposase-accessible chromatin sequencing (ATAC-Seq) in SCCM and control patients. Further validation was conducted for the gene of interest using qPCR and RNA in situ hybridization (RNA FISH) techniques to provide further atlas and evidence for SCCM generative process. We identified six cell types in the SCCM and control vessels and found that the expression of NEK1 , RNPC3 , FBRSL1 , IQGAP2 , MCUB , AP3B1 , ESCO1 , MYO9B and PVT1 were up-regulated in SCCM tissues. Among the six cell types, we found that compared with control conditions, PVT1 showed a rising peak which followed the pseudo-time axis in endothelial cell clusters of SCCM samples, while showed an increasing trend in smooth muscle cell clusters of SCCM samples. Further experiments indicated that, compared with the control vessels, PVT1 exhibited significantly elevated expression in SCCM samples. In SCCM conditions, We found that in the process of development from control to lesion conditions, PVT1 showed a rising peak in endothelial cells and showed an increasing trend in smooth muscle cells at the same time. Overall, there was a significantly elevated expression of NEK1, RNPC3, FBRSL1, IQGAP2, MCUB, AP3B1, ESCO1, MYO9B and PVT1 in SCCM specimens compared to control samples. [ABSTRACT FROM AUTHOR]

Abstract We report a patient initially diagnosed with a triple hit high‐grade B cell lymphoma (HGBL‐TH), in which further morphologic, immunohistochemical, and next‐generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC‐DLBCL) with BCL2/BCL6 gene translocations, PVT1‐deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break‐apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH‐lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double‐hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas.

Plasmacytoma variant translocation 1 (PVT1) is involved in multiple signaling pathways and plays an important regulatory role in a variety of malignant tumors. However, its role in the prognosis and immune invasion of bladder urothelial carcinoma (BLCA) remains unclear. This study investigated the expression of PVT1 in tumor tissue and its relationship with immune invasion, and determined its prognostic role in patients with BLCA. Patients were identified from the cancer genome atlas (TCGA). The enrichment pathway and function of PVT1 were explained by gene ontology (GO) term analysis, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA), and the degree of immune cell infiltration was quantified. Kaplan–Meier analysis and Cox regression were used to analyze the correlation between PVT1 and survival rate. PVT1-high BLCA patients had a lower 10-year disease-specific survival (DSS P < 0.05) and overall survival (OS P < 0.05). Multivariate Cox regression analysis showed that PVT1 (high vs. low) (P = 0.004) was an independent prognostic factor. A nomogram was used to predict the effect of PVT1 on the prognosis. PVT1 plays an important role in the progression and prognosis of BLCA and can be used as a medium biomarker to predict survival after cystectomy.

Abstract The role of circular RNAs in oncogenesis has begun to be widely studied in recent years, due to the significant impact that these molecules have in disease pathogenesis, as well as their potential for the future of innovative therapies. Moreover, due to their characteristically circular shape, circular RNAs are very resistant molecules to RNA degradation whose levels are easily assessed in body fluids. Accordingly, they represent an opportunity for the discovery of new diagnostic and prognostic markers in a wide range of diseases. Among circular RNAs, circPVT1 is a rather peculiar one that originates from the circularization of the exon 2 of the PVT1 gene that encodes a pro-tumorigenic long non-coding RNA named lncPVT1. There are a few examples of circular RNAs that derive from a locus producing another non-coding RNA. Despite their apparent transcriptional independence, which occurs using two different promoters, a possible synergistic effect in tumorigenesis cannot be excluded considering that both have been reported to correlate with the oncogenic phenotype. This complex mechanism of regulation appears to also be controlled by c-MYC. Indeed, the PVT1 locus is located only 53 Kb downstream c-MYC gene, a well-known oncogene that regulates the expression levels of about 15% of all genes. Here, we review circPVT1 origin and biogenesis highlighting the most important mechanisms through which it plays a fundamental role in oncogenesis, such as the well-known sponge activity on microRNAs, as well as its paradigmatic interactome link with lncPVT1 and c-MYC expression.

Background: N6-methyladenosine (m6A) is the most common posttranscriptional modification of RNA and plays critical roles in human cancer progression. However, the biological function of m6A methylation requires further studied in cancer, especially in tumor angiogenesis. Methods: A public database was used to analyze the expression and overall survival of ALKBH5 and PVT1 in lung cancer patients. CCK-8 and colony formation assays were performed to detect cell proliferation, a transwell assay was used to assess cell migration, and a tube formation assay was performed to assess angiogenic potential in vitro. A zebrafish lung cancer xenograft model was used to verify the function of ALKBH5 and PVT1 in vivo. Western blot assays were used to measure the relative protein expression in lung cancer cells. SRAMP predictor analysis and RNA stability experiments were used to examine the potential m6A modification. Results: Bioinformatics analysis showed that the expression levels of m6A-related genes were changed significantly in lung cancer tissues compared with normal lung tissues. We then identified that ALKBH5 was upregulated in lung cancer tissues and associated with poor prognosis of lung cancer patients by analyzing a public database. Knockdown of ALKBH5 inhibited the proliferation and migration of cultured lung cancer cell lines. Zebrafish lung cancer xenografts showed that ALKBH5 silencing also suppressed the growth and metastasis of lung cancer cells. Moreover, knockdown of ALKBH5 inhibited the angiogenesis of lung cancer in vitro and in vivo. Mechanistic studies showed that knockdown of ALKBH5 decreased the expression and stability of PVT1 in lung cancer cells. We next observed that PVT1 promoted the progression of lung cancer cells in vitro and in vivo and regulated the expression of VEGFA and angiogenesis in lung cancer. Finally, rescue experiments revealed that ALKBH5 regulated the proliferation, migration and angiogenesis of lung cancer cells, partially through PVT1. Conclusion: Our results demonstrate that ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the expression and stability of PVT1, which provides a potential prognostic and therapeutic target for lung cancer patients. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs are involved in epigenetic gene modification, including binding to the chromatin rearrangement complex in pre-transcriptional regulation and to gene promoters in gene expression regulation, as well as acting as microRNA sponges to control messenger RNA levels in post-transcriptional regulation. An increasing number of studies have found that long noncoding RNA plasmacytoma variant translocation 1 (PVT1) plays an important role in cancer development. In this review of a large number of studies on PVT1, we found that PVT1 is closely related to tumor onset, proliferation, invasion, epithelial–mesenchymal transformation, and apoptosis, as well as poor prognosis and radiotherapy and chemotherapy resistance in some cancers. This review comprehensively describes PVT1 expression in various cancers and presents novel approaches to the diagnosis and treatment of cancer. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are critical in regenerating tissues because they can differentiate into various tissue cells. MSCs interact closely with cells in the tissue microenvironment during the repair of damaged tissue. Although regarded as non-healing wounds, tumors can be treated by MSCs, which showed satisfactory treatment outcomes in previous reports. However, it is largely unknown whether the biological behaviors of MSCs would be affected by the tumor microenvironment. Exploring the truth of tumor microenvironmental cues driving MSCs tumor "wound" regeneration would provide a deeper understanding of the biological behavior of MSCs. Therefore, we mimicked the tumor microenvironment using co-cultured glioma C6 cells and rat MSCs, aiming to assess the proliferation and migration of MSCs and the associated effects of Stat3 in this process. The results showed that co-cultured MSCs significantly exhibited enhanced tumorigenic, migratory, and proliferative abilities. Both up-regulation of Stat3 and down-regulation of miR-134-5p were detected in co-cultured MSCs. Furthermore, miR-134-5p directly regulated Stat3 by binding to the sequence complementary to microRNA response elements in the 3′-UTR of its mRNA. Functional studies showed that both the migration and proliferation abilities of co-cultured MSCs were inhibited by miR-134-5p, whereas Stat3 gain-of-function treatment reversed these effects. In addition, Pvt1 was confirmed to be regulated by miR-134-5p through Stat3 and the suppression of Pvt1 reduced the migration and proliferation abilities of co-cultured MSCs. To sum up, these results demonstrate a suppressive role of miR-134-5p in tumor-environment-driven malignant transformation of rat MSCs through directly targeting Stat3, highlighting a crucial role of loss-of-function of miR-134-5p/Stat3 axis in the malignant transformation, providing a reference to the potential clinic use of MSCs. [ABSTRACT FROM AUTHOR]

Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the c-MYC proto-oncogene (MYC) and its downstream targets in tumor samples. We identified tumors with high and low differential MYC expression and found patients with high-MYC tumors were older and overweight or obese. We also detected elevated expression of the PVT1 long-non-coding RNA (lncRNA) in most tumors and found gains in copy number for both MYC and PVT1 gene loci in 35% of tumors evaluated. Our transcriptome analyses indicate that EOCRC can be sub-classified into groups based on differential MYC expression and suggest that deregulated MYC contributes to CRCs that develop in younger patients. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder characterized by the formation of kidney cysts that originate from the epithelial tubules of the nephron and primarily results from mutations in polycystin-1 (PKD1) and polycystin-2 (PKD2). The metanephric organ culture (MOC) is an ex vivo system in which explanted embryonic kidneys undergo tubular differentiation and kidney development. MOC has been previously used to study polycystic kidney disease as treatment with 8-bromo-cAMP induces the formation of kidney cysts. However, the inefficiency of manipulating gene expression in MOC has limited its utility for identifying genes and pathways that are involved in cystogenesis. Here, we used a lentivirus and three serotypes of self-complementary adeno-associated viral (scAAV) plasmids that express green fluorescent protein and found that scAAV serotype D/J transduces the epithelial compartment of MOC at an efficiency of 68%. We used scAAV/DJ to deliver shRNA to knockdown Pvt1, a long noncoding RNA, which was upregulated in kidneys from Pkd1 and Pkd2 mutant mice and humans with ADPKD. shRNA delivery by scAAV/DJ downregulated expression of Pvt1 by 45% and reduced the cyst index by 53% in wild-type MOCs and 32% in Pkd1-null MOCs. Knockdown of Pvt1 decreased the level of c-MYC protein by 60% without affecting Myc mRNA, indicating that Pvt1 regulation of c-MYC was posttranscriptional. These results identify Pvt1 as a long noncoding RNA that modulates cyst progression in MOC. NEW & NOTEWORTHY This study identified scAAV/DJ as effective in transducing epithelial cells of the metanephric organ culture (MOC). We used scAAV/DJ shRNA to knockdown Pvt1 in cystic MOCs derived from Pkd1-null embryos. Downregulation of Pvt1 reduced cyst growth and decreased levels of c-MYC protein. These data suggest that suppression of Pvt1 activity in autosomal dominant polycystic kidney disease might reduce cyst growth. [ABSTRACT FROM AUTHOR]

Introduction: Human oral squamous cell carcinoma (OSCC) is the most common type of oral cancer and has a poor survival rate. Cell-cell communication between OSCC cells and cancer-associated fibroblasts (CAFs) plays important roles in OSCC progression. We previously demonstrated that CAFs promote OSCC cell migration and invasion. However, how OSCC cells influence CAFs proliferation is unknown., Methods: Knockdown of PVT1 was confirmed using lentivirus infection technique. CAFs in tissues were identified by staining the cells with α-SMA using immunohistochemical technique. CCK-8 assay was used to evaluate cell proliferation. The mRNA level of a gene was measured by qRT-PCR. Secreted TGF-β were detected using ELISA assay., Results: We found that knockdown of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was associated with a low density of CAFs in xenograft tumors in mice; further analysis revealed that PVT1 in OSCC cells induced CAF proliferation through transforming growth factor (TGF)-β., Discussion: Our results demonstrate that lncRNA PVT1 in tumor cells participates in CAF development in OSCC by regulating TGF-β. This study revealed a new mechanism by which PVT1 regulates OSCC progression and PVT1 is a potential therapeutic target in OSCC.

Han Zhang,1 Qinghui Niu,1 Kun Liang,2 Xuesen Li,3 Jing Jiang,2 Cheng Bian2 1Department of Liver Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 3Department of Spine Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Qinghui NiuDepartment of Liver Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266100, People’s Republic of ChinaTel +86-0532-82915998Email qinghuiniu@163.comPurpose: Nonalcoholic fatty liver disease (NAFLD) is closely related to lipid metabolism and insulin resistance. The current research mainly attempted to verify the clinical value of LncRNA plasmacytoma variant translocation 1 (PVT1), and whether microRNA regulates lipid metabolism and insulin resistance to participate in NAFLD.Patients and Methods: 81 patients with NAFLD and 78 healthy individuals were enrolled in this study. In addition, C57BL/6 mice were fed a high-fat diet to establish NAFLD model in vivo. Serum PVT1 and miR-20a-5p expression in NAFLD patients and mice were assessed by RT-qPCR. ROC curves determine the diagnostic value of PVT1 and miR-20a-5p. NAFLD mice were subjected to IPGTT to detect changes in insulin sensitivity, and the common indicators of lipid metabolism and insulin resistance were also evaluated. Dual-luciferase reporter assay verified the regulation mechanism of PVT1 and miR-20a-5p.Results: PVT1 was upregulated in NAFLD patients and mice, while miR-20a-5p was decreased. Their expression trends were similar in patients with HOMA-IR ≥ 2.5. What’s more, miR-20a-5p, FBG, ALT, and HOMA-IR were independently correlated with PVT1. And PVT1 and miR-20a-5p show high clinical diagnostic value. Bodyweight, insulin sensitivity, lipid metabolism inductors were increased in NAFLD mice, but these increases were attenuated by PVT1 elimination. Finally, miR-20a-5p might function as the possible miRNA target of PVT1 via the binding sites at 3ʹ-UTR and negatively regulated by it.Conclusion: PVT1 and miR-20a-5p are potential clinical biomarkers of NAFLD, and PVT1 promotes the occurrence of NAFLD by regulating insulin sensitivity and lipid metabolism, which may be achieved by targeting miR-20a-5p.Keywords: PVT1, miR-20a-5p, NAFLD, insulin sensitivity, lipid metabolism

Abstract Background Congestive heart failure (CHF) is a major cause of the development of progressive chronic kidney disease (CKD), while the mechanism is still unknown. LncRNA PVT1 contributes to kidney injury. This study aimed to explore the role of PVT1 in the development of CKD in CHF patients. Methods Expression of PVT1 in plasma samples of CHF patients with and without CKD was determined by RT-qPCR. The diagnostic value of plasma PVT1 for CKD was evaluated by ROC curve analysis. The predictive value of PVT1 for the development of CKD in CHF patients was analyzed by a 2-year follow-up study. Changes in PVT1 expression in CKD patients during treatment were analyzed by RT-qPCR and reflected by heatmaps. Results Plasma PVT1 was downregulated in CHF and further downregulated in CHF patients complicated with progressive CKD. ROC curve analysis showed that plasma PVT1 levels could be used to distinguish CHF patients complicated with CKD from CHF patients without CKD and healthy controls. During a 2-year follow-up, patients with high CHF levels had a low incidence of progressive CKD among CHF patients. Moreover, with the treatment of progressive CKD, plasma PVT1 was upregulated. Conclusions LncRNA-PVT1 downregulation may participate in the development of progressive CKD among patients with CHF.

Cancer is fundamentally a genetic disorder that alters cellular information flow toward aberrant growth. The coding part accounts for less than 2% of the human genome, and it has become apparent that aberrations within the noncoding genome drive important cancer phenotypes. The numerous carcinogenesis-related genomic variations in the 8q24 region include single nucleotide variations (SNVs), copy number variations (CNVs), and viral integrations occur in the neighboring areas of the MYC locus. It seems that MYC is not the only target of these alterations. The MYC-proximal mutations may act via regulatory noncoding RNAs (ncRNAs). In this study, gene expression analyses indicated that the expression of some PVT1 spliced linear transcripts, CircPVT1, CASC11, and MYC is increased in colorectal cancer (CRC). Moreover, the expression of these genes is associated with some clinicopathological characteristics of CRC. Also, in vitro studies in CRC cell lines demonstrated that CASC11 is mostly detected in the nucleus, and different transcripts of PVT1 have different preferences for nuclear and cytoplasmic parts. Furthermore, perturbation of PVT1 expression and concomitant perturbation in PVT1 and CASC11 expression caused MYC overexpression. It seems that transcription of MYC is under regulatory control at the transcriptional level, i.e., initiation and elongation of transcription by its neighboring genes. Altogether, the current data provide evidence for the notion that these noncoding transcripts can significantly participate in the MYC regulation network and in the carcinogenesis of colorectal cells. [ABSTRACT FROM AUTHOR]