lncRNA PVT1 Research Articles

Long Non-Coding RNA PVT1 Facilitates Radiation-Induced Vascular Endothelial Cell Injury through Sponging MicroRNA-9-5p.

Radiotherapy is a common therapeutic strategy for various solid tumors, with vascular endothelial injury being a common side effect. The study aimed to examine the effect of long non-coding RNA PVT1 on radiation-induced vascular endothelial cell injury, and explore the possible underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were exposed to different doses of X ray to mimic radiation. LncRNA and miRNA levels were detected via qRT-PCR. Interaction between lncRNA and miRNAs was determined through dual-luciferase reporter assay. Statistical processing was conducted using student's t test between two groups and one-way ANOVA among multiple groups, and P < 0.05 means a significant difference. GO and KEGG were performed for the function and pathway enrichment analysis. LncRNA PVT1 elevated along with the increase of radiation dose in HUVECs. Poorly expressed lncRNA PVT1 promotes cell viability and inhibits oxidative stress. PVT1 serves as a competitive endogenous RNA (ceRNA) of miR-9-5p. miR-9-5p inhibitor inverted the influence of PVT1 knockdown on radiation-stimulated cell apoptosis and oxidative stress in HUVECs. KEGG analysis identified significant enrichment of the MAPK signaling pathway among overlapping target genes of miR-9-5p. LncRNA PVT1 knockdown alleviated radiation-induced vascular endothelial injury via sponging miR-9-5p. The underlying mechanism might be probably MAPK signaling-related.

LncRNA Pvt1 aggravates cardiomyocyte apoptosis via the microRNA-216/Ccnd3 axis

ObjectiveOur study aims to evaluate the role of long non-coding RNA variant translocation gene Pvt1 in cardiomyocyte apoptosis, as well as the potential targets and mechanisms involved in Pvt1-miRNA-mRNA axis. Methods1.Pvt1 knockdown in cells by transfection with small interfering RNA (si-Pvt1), HL-1 cells were randomly divided into control group, hypoxia group, hypoxia + negative control group and hypoxia + si-Pvt1 group. Apoptosis-related genes expression was detected by Western blot assay, RT-qPCR and Flow cytometry assay. 2.Pvt1 knockdown model (sh-Pvt1) was established by injecting adeno-associated virus (AAV) vector shRNA-Pvt1 into the caudal vein 7 days before myocardial infarction, and echocardiography was used to measure cardiac function 7 days after myocardial infarction induced by ligation of the left anterior descending branch. HE staining was used to evaluate the pathological injury of mouse heart tissue, and the apoptotic protein expression was detected by Western blot. 3.lncRNA-related microRNAs were predicted by bioinformatics tools and further verified by dual luciferase experiment. Western blot analysis was used to identify the expression of apoptotic genes following the simultaneous transfection of si-Pvt1 and miR-216 mimics. Genes differentially expressed in hypoxia + si-NC and hypoxia + si-Pvt1 groups were identified by RNA sequencing. These genes were then compared with the target genes of miR-216 predicted by bioinformatics tools. The gene of interest Ccnd3 was excluded from the analysis. Western blot analysis was used to assess the expression of Apoptosis-related proteins in HL-1 cells co-transfected with miR-216 mimics and overexpressed Ccnd3. Results1. Pvt1 was highly expressed in HL-1 induced by hypoxia, and Pvt1 knockdown can reduce cell apoptosis in hypoxia cells. 2. MI causes myocardial injury in mice, and inhibition of Pvt 11 can improve the cardiac function of mice with myocardial infarction, prevent some inflammatory cell infiltration, and reduce myocardial cell apoptosis. 3. Pvt1 acts as a sponge for miR-216 and promotes the expression of Ccnd3. ConclusionPvt1 may promote myocardial infarct-induced apoptosis through the miR-216/Ccnd3 axis.

LncRNA PVT1 silencing inhibits gastric cancer cells’ progression via enhancing chemosensitivity to paclitaxel

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide because of its high morbidity and the absence of effective therapies. Even though paclitaxel is a powerful anticancer chemotherapy drug, recent studies have indicated its ineffectiveness against GC cells. Long non-coding RNA (lncRNA) PVT1 has a high expression in GC cells and increases the progression of tumors via inducing drug resistance. In the present study, the effects of the siRNA-mediated lncRNA PVT1 gene silencing along with paclitaxel treatment on the rate of apoptosis, growth, and migration of AGS GC cells were investigated. AGS cells were cultured and then transfected with siRNA PVT1 using electroporation. The MTT test was used to examine the effect of treatments on the viability of cultured cells. Furthermore, the flow cytometry method was used to evaluate the impact of treatments on the cell cycle process and apoptosis induction in GC cells. Finally, the mRNA expression of target genes was assessed using the qRT-PCR method. The results showed that lncRNA PVT1 gene suppression, along with paclitaxel treatment, reduces the viability of cancer cells and significantly increases the apoptosis rate of cancer cells and the number of cells arrested in the G2/M phase compared to the control group. Based on the results of qRT-PCR, combined treatment significantly decreased the expression of MMP3, MMP9, MDR1, MRP1, Bcl-2, k-Ras, and c-Myc genes and increased the expression of the Bax gene compared to the control group. The results of our study showed that lncRNA PVT1 gene targeting, together with paclitaxel treatment, induces apoptosis, inhibits growth, alleviates drug resistance, and reduces the migratory capability of GC cells. Therefore, there is a need for further investigations to evaluate the feasibility and effectiveness of this approach in vivo in animal models.

Lnc PVT1 facilitates TGF-β1-induced human cardiac fibroblast activation in vitro and ISO-induced myocardial fibrosis in vivo through regulating MYC.

Cardiac fibrosis is a commonly seen pathophysiological process in various cardiovascular disorders, such as coronary heart disorder, hypertension, and cardiomyopathy. Cardiac fibroblast trans-differentiation into myofibroblasts (MFs) is a key link in myocardial fibrosis. LncRNA PVT1 participates in fibrotic diseases in multiple organs; however, its role and mechanism in cardiac fibrosis remain largely unknown. Human cardiac fibroblasts (HCFs) were stimulated with TGF-β1 to induce myofibroblast; Immunofluorescent staining, Immunoblotting, and fluorescence in situ hybridization were used to detect the myofibroblasts phenotypes and lnc PVT1 expression. Cell biological phenotypes induced by lnc PVT1 knockdown or overexpression were detected by CCK-8, flow cytometry, and Immunoblotting. A mouse model of myocardial fibrosis was induced using isoproterenol (ISO), and the cardiac functions were examined by echocardiography measurements, cardiac tissues by H&E, and Masson trichrome staining. In this study, TGF-β1 induced HCF transformation into myofibroblasts, as manifested as significantly increased levels of α-SMA, vimentin, collagen I, and collagen III; the expression level of lnc PVT1 expression showed to be significantly increased by TGF-β1 stimulation. The protein levels of TGF-β1, TGFBR1, and TGFBR2 were also decreased by lnc PVT1 knockdown. Under TGF-β1 stimulation, lnc PVT1 knockdown decreased FN1, α-SMA, collagen I, and collagen III protein contents, inhibited HCF cell viability and enhanced cell apoptosis, and inhibited Smad2/3 phosphorylation. Lnc PVT1 positively regulated MYC expression with or without TGF-β1 stimulation; MYC overexpression in TGF-β1-stimulated HCFs significantly attenuated the effects of lnc PVT1 knockdown on HCF proliferation and trans-differentiation to MFs. In the ISO-induced myocardial fibrosis model, lnc PVT1 knockdown partially reduced fibrotic area, improved cardiac functions, and decreased the levels of fibrotic markers. In addition, lnc PVT1 knockdown decreased MYC and CDK4 levels but increased E-cadherin in mice heart tissues. lnc PVT1 is up-regulated in cardiac fibrosis and TGF-β1-stimulated HCFs. Lnc PVT1 knockdown partially ameliorates TGF-β1-induced HCF activation and trans-differentiation into MFs in vitro and ISO-induced myocardial fibrosis in vivo, potentially through interacting with MYC and up-regulating MYC.

Upregulation of the long noncoding RNA GJA9-MYCBP and PVT1 is a potential diagnostic biomarker for acute lymphoblastic leukemia.

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. 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. 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 <.0001), suggesting that lncRNA GJA9-MYCBP and PVT1 may serve as a diagnostic biomarker for ALL. Linear regression analysis unveiled positive correlations between the expression level of MYC and lncRNA GJA9-MYCBP and PVT1 in ALL patients (p-values <.01). In this study, we provided approval for the clinical diagnostic significance of lncRNA GJA9-MYCBP and PVT1that their upregulations may be a diagnostic biomarker for ALL.

Sparassis latifolia and exercise training as complementary medicine mitigated the 5-fluorouracil potent side effects in mice with colorectal cancer: bioinformatics approaches, novel monitoring pathological metrics, screening signatures, and innovativemanagement tactic.

Prompt identification and assessment of the disease are essential for reducing the death rate associated with colorectal cancer (COL). Identifying specific causal or sensitive components, such as coding RNA (cRNA) and non-coding RNAs (ncRNAs), may greatly aid in the early detection of colorectal cancer. For this purpose, we gave natural chemicals obtained from Sparassis latifolia (SLPs) either alone or in conjunction with chemotherapy (5-Fluorouracil to a mouse colorectal tumor model induced by AOM-DSS. The transcription profile of non-coding RNAs (ncRNAs) and their target hub genes was evaluated using qPCR Real-Time, and ELISA techniques. MSX2, MMP7, ITIH4, and COL1A2 were identified as factors in inflammation and oxidative stress, leading to the development of COL. The hub genes listed, upstream regulatory factors such as lncRNA PVT1, NEAT1, KCNQ1OT1, SNHG16, and miR-132-3p have been discovered as biomarkers for prognosis and diagnosis of COL. The SLPs and exercise, effectively decreased the size and quantity of tumors. This effect may be attributed to the modulation of gene expression levels, including MSX2, MMP7, ITIH4, COL1A2, PVT1, NEAT1, KCNQ1OT1, SNHG16, and miR-132-3p. Ultimately, SLPs and exercise have the capacity to be regarded as complementing and enhancing chemotherapy treatments, owing to their efficacious components.

Retraction: "Silencing lncRNA PVT1 inhibits activation of astrocytes and increases BDNF expression in hippocampus tissues of rats with epilepsy by downregulating the Wnt signaling pathway".

Retraction: "Silencing lncRNA PVT1 inhibits activation of astrocytes and increases BDNF expression in hippocampus tissues of rats with epilepsy by downregulating the Wnt signaling pathway", by Teng Zhao, Ying Ding, Min Li, Chunkui Zhou, and Weihong Lin, J Cell Physiol. 2019; 234: 16054-16067: The above article, published online on 25 February 2019 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.28264) has been retracted by agreement between the journal's Editor in Chief, Alexander Hutchison, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found. Furthermore, indication for image manipulation was found in Figures 3, 7, and 9. Thus, the editors consider the conclusions of this article to be invalid.

Retracted: LncRNA PVT1 Promotes Hypoxia-Induced Cardiomyocyte Injury by Inhibiting miR-214-3p.

[This retracts the article DOI: 10.1155/2021/4604883.].

LncRNA PVT1 as a Novel Biomarker for Diabetes-related Complications.

Diabetes is now afflicting an expanding population, and it has become a major source of concern for human health. Diabetes affects several organs and causes chronic damage and dysfunction. It is one of the three major diseases that are harmful to human health. Plasmacytoma variant translocation 1 is a member of long non-coding RNA. PVT1 expression profile abnormalities have been reported in diabetes mellitus and its consequences in recent years, suggesting that it may contribute to the disease's progression. Relevant literature from the authoritative database "PubMed" are retrieved and summarized in detail. Mounting evidence reveals that PVT1 has multiple functions. Through sponge miRNA, it can participate in a wide variety of signal pathways and regulate the expression of a target gene. More importantly, PVT1 is crucially implicated in the regulation of apoptosis, inflammation, and so on in different types of diabetes-related complications. PVT1 regulates the occurrence and progression of diabetes-related diseases. Collectively, PVT1 has the potential to be a useful diagnostic and therapeutic target for diabetes and its consequences.

LncRNA PVT1 promotes neuroinflammation after intracerebral hemorrhage by regulating the miR-128-3p/TXNIP axis

Objective Intracerebral hemorrhage (ICH) has significant morbidity and mortality. TXNIP and the competing endogenous RNA (ceRNA) regulatory mechanism involved in long non-coding RNA (lncRNA) play roles in ICH. We probed the upstream microRNAs (miRNAs)/lncRNAs that regulated TXNIP expression in the ceRNA mechanism. Methods ICH mouse model was established, and ICH secondary injury was simulated in BV2 microglia by hemin treatment. TXNIP was silenced 48 h before ICH modeling. The ICH mouse brain water content (BWC) and brain lesion volume after ICH were recorded. Neuronal apoptosis and neurological deficits were evaluated by double staining of NeuN and TUNEL/modified Garcia/corner turn/forelimb placement tests. Iba1 + microglia number and tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/IL-10/TXNIP/PVT1/miR-128-3p levels were assessed by immunohistochemistry, Western blot, ELISA, and RT-qPCR. Cell viability/death of BV2 cells conditioned medium-treated neuron HT22 cells were assessed by CCK-8/LDH assays. miRNA that had a targeted binding relationship with TXNIP was screened. The targeted bindings of miR-128-3p to TXNIP/PVT1 to miR-128-3p were verified by dual-luciferase reporter gene assay. Results TXNIP knockdown reduced post-ICH microglial activation/release of pro-inflammatory factors/brain edema/brain lesion volume/neurological deficits in mice and increased releases of anti-inflammatory factors. TXNIP/PVT1 knockdown inhibited hemin-induced inflammatory responses in BV2 cells and protected in vitro co-cultured HT22 cells. PVT1 was a sponge of miR-128-3p to repress TXNIP expression. miR-128-3p knockdown diminished PVT1 knockdown-inhibited hemin-induced BV2 cell inflammatory responses/neurotoxicity. Conclusions PVT1 silencing reduced hemin-induced neuroinflammation and had a protective effect on neurons by increasing the targeted inhibition of TXNIP by miR-128-3p.

Transcription regulation by long non-coding RNAs:mechanisms and disease relevance.

Long non-coding RNAs (lncRNAs) outnumber protein-coding transcripts, but their functions remain largely unknown. In this Review, we discuss the emerging roles of lncRNAs in the control of gene transcription. Some of the best characterized lncRNAs have essential transcriptioncis-regulatory functions that cannot be easily accomplished by DNA-interacting transcription factors, such as XIST, which controls X-chromosome inactivation, or imprinted lncRNAs that direct allele-specific repression. A growing number of lncRNA transcription units, including CHASERR, PVT1 and HASTER(also known asHNF1A-AS1) act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes that encode transcription factors. Genetic experiments have shown that defects in such transcription stabilizers often cause severe phenotypes. Other lncRNAs, such as lincRNA-p21 (also known asTrp53cor1)and Maenli(Gm29348) contribute to local activation of gene transcription, whereas distinct lncRNAs influence gene transcription in trans. We discuss findings of lncRNAs that elicit a function through either activation of their transcription, transcript elongation and processing or the lncRNA molecule itself. We also discuss emerging evidence of lncRNA involvement in human diseases, and their potential as therapeutic targets.

UPF1 Participates in the Progression of Endometrial Cancer by Inhibiting the Expression of lncRNA PVT1 [Retraction

[This retracts the article DOI: 10.2147/OTT.S233149.].

Genomic Analysis of Lymphoma Risk in Bullmastiff Dogs.

Lymphoma is the most common haematological malignancy affecting dogs and has a high incidence in the Bullmastiff breed. The aim of this study was to identify risk loci predisposing this breed to the disease. The average age of lymphoma diagnosis in 55 cases was less than 6 years, similar to the median age of 64 cases from our clinical and pathology databases. When fine-scale population structure was explored using NETVIEW, cases were distributed throughout an extended pedigree. When genotyped cases (n = 49) and dogs from the control group (n = 281) were compared in a genome-wide association analysis of lymphoma risk, the most prominent associated regions were detected on CFA13 and CFA33. The top SNPs in a 5.4 Mb region on CFA13 were significant at a chromosome-wide level, and the region was fine-mapped to ~1.2 Mb (CFA13: 25.2-26.4 Mb; CanFam3.1) with four potential functional candidates, including the MYC proto-oncogene bHLH transcription factor (MYC) and a region syntenic with the human and mouse lncRNA Pvt1 oncogene (PVT1). A 380 Kb associated region at CFA33: 7.7-8.1 Mb contained the coding sequence for SUMO specific peptidase7 (SENP7) and NFK inhibitor zeta (NFKBIZ) genes. These genes have annotations related to cancer, amongst others, and both have functional links to MYC regulation. Genomic signatures identified in lymphoma cases suggest that increased risk contributed by the regions identified by GWAS may complement a complex predisposing genetic background.

Knockdown of lncRNA PVT1 protects human trabecular meshwork cells against H2O2-induced injury via the regulation of the miR-29a-3p/VEGF/MMP-2 axis

PurposeHuman trabecular meshwork cell (HTMC) dysfunction results in imbalanced aqueous humor inflow and outflow, leading to an increase in intraocular pressure (IOP). Uncontrolled high IOP can promote the occurrence of glaucoma, an irreversible optic neuropathy. Here, we explored whether the long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1)/microRNA-29a-3p (miR-29a-3p) axis could ameliorate HTMC dysfunction under oxidative stress by modulating the expression of the proangiogenic factor vascular endothelial growth factor (VEGFA) and the profibrotic factor metalloproteinase-2 (MMP-2). MethodsHTMCs were cultured under H2O2-induced oxidative stress for 48 h. The expression of lncRNA PVT1, miR-29a-3p, VEGFA, MMP-2, intracellular adhesion molecule-1 (ICAM-1), and alpha-smooth muscle actin (α-SMA) was detected by reverse transcription quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. Interference experiments were conducted via the transfection of HTMCs with small interfering RNA (siRNA) targeting lncRNA PVT1 or miR-29a-3p mimics. A luciferase reporter assay was undertaken to identify the presence of a miR-29a-3p binding site in lncRNA PVT1. Flow cytometry and Transwell and Cell Counting Kit-8 assays were employed to evaluate HTMC functions under oxidative stress with different treatments. ResultsIn HTMCs, the expression of lncRNA PVT1 was induced by H2O2 treatment, whereas that of miR-29a-3p was inhibited. The levels of angiogenic factors (VEGFA, ICAM-1) and fibrosis-associated mediators (MMP-2, α-SMA) were upregulated in HTMCs under oxidative stress. The siRNA-mediated suppression of lncRNA PVT1 or the upregulation of miR-29a-3p significantly suppressed the expression of VEGFA, MMP-2, ICAM-1, and α-SMA. A luciferase reporter assay confirmed that lncRNA PVT1 directly targeted miR-29a-3p and acted as a miR-29a-3p sponge. The knockdown of lncRNA PVT1 restored the level of miR-29a-3p in H2O2-treated HTMCs, thereby inhibiting VEGFA and MMP-2, its target mRNAs. HTMC dysfunction, including increased apoptosis and decreased cell mobility and viability, could be effectively ameliorated by lncRNA PVT1 downregulation or miR-29a-3p overexpression under oxidative stress. ConclusionLncRNA PVT1 has potential as a therapeutic target for inhibiting VEGFA and MMP-2, thus protecting HTMCs, suppressing the progression of fibrosis, and, consequently, improving the outcome of glaucoma filtration surgery.

Investigation of LncRNA PVT1 and MiR-21-5p Expression as Promising Novel Biomarkers for Autism Spectrum Disorder.

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.

Expression level and clinical significance of LncRNA PVT1 in the serum of patients with LEASO.

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. 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 (n=48) and double (n=41) lower limb groups, with the former being subclassified into the left (n=28) and right (n=20) 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. It was found that lncRNA PVT1 expression was the highest in the serum of the LEASO with CAD group, 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 = 2.972, 95% CI [1.159-7.618]), cholesterol (OR = 6.655, 95% CI [1.490-29.723]), C-reactive protein (OR = 1.686, 95% CI [1.218-2.335]), and PVT1 (OR = 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. 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.

Deoxynivalenol upregulates hypoxia-inducible factor-1α to promote an "immune evasion" process by activating STAT3 signaling.

Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.

Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes

ObjectiveThis study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA).MethodsBMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles.ResultsA total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The “has-miR-424-5p/lncRNA PVT1” was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes.ConclusionIL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.

LncRNA PVT1 promotes strong stemness and endothelial progenitor cell characteristics in renal carcinoma stem cells.

Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.

LncRNA PVT1 promotes bladder cancer progression by forming a positive feedback loop with STAT5B

BackgroundPlasmacytoma Variant Translocation 1 (LncRNA PVT1) and signal transducer and activator of transcription 5B (STAT5B) play important roles in various cancers, but their interaction in bladder cancer (BC) remains unclear. PurposeWe aimed to explore the interaction between lncRNA PVT1 and STAT5B in BC tumorigenesis and find potential drugs for BC. MethodsThe association of the expression of lncRNA PVT1 and STAT5B to the prognosis of BC patients was evaluated via bioinformatic analysis. Loss- and gain-of-function assays were performed to determine the biological functions of lncRNA PVT1 and STAT5B. Quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence were used to detect lncRNA PVT1 and STAT5B expression. Fluorescence in situ hybridization, RNA pull-down and RNA immunoprecipitation assays were conducted to determine the regulatory effect of lncRNA PVT1 on STAT5B. The transcriptional effect of STAT5B on lncRNA PVT1 gene was determined using luciferase reporter assay, chromatin immunoprecipitation and DNA-affinity precipitation assays. Connectivity Map analysis was used to screen anticancer drugs. ResultsLncRNA PVT1 and STAT5B enhance the expression of each other and promote the malignant phenotypes in BC, including cell viability and invasion. lncRNA PVT1 stabilizes STAT5B by decreasing ubiquitination, enhances STAT5B phosphorylation, and promotes the translocation to the nucleus of STAT5B to trigger further carcinogenesis activities. In the nucleus, STAT5B activates the transcription of lncRNA PVT1 by binding directly to its promoter region, leading to a positive feedback. Tanespimycin effectively abated the oncogenic effect. ConclusionsWe first identified the lncRNA PVT1/STAT5B positive feedback loop for bladder carcinogenesis, and found a potentially effective drug for BC.