Plasmacytoma Variant Translocation Research Articles

PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma

BackgroundSorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC), yet its effectiveness is often constrained. Emerging studies reveal that sorafenib triggers ferroptosis, an iron-dependent regulated cell death (RCD) mechanism characterized by lipid peroxidation. Our findings isolate the principal target responsible for ferroptosis in HCC cells and outline an approach to potentially augment sorafenib's therapeutic impact on HCC.MethodsWe investigated the gene expression alterations following sgRNA-mediated knockdown induced by erastin and sorafenib in HCC cells using CRISPR screening-based bioinformatics analysis. Gene set enrichment analysis (GSEA) and the "GDCRNATools" package facilitated the correlation studies. We employed tissue microarrays and cDNA microarrays for validation. Ubiquitination assay, Chromatin immunoprecipitation (ChIP) assay, RNA immunoprecipitation (RIP) assay, and dual-luciferase reporter assay were utilized to delineate the specific mechanisms underlying ferroptosis in HCC cells.ResultsOur study has revealed that pleiomorphic adenoma gene 1 (PLAG1), a gene implicated in pleomorphic adenoma, confers resistance to ferroptosis in HCC cells treated with sorafenib. Sorafenib leads to the opposite trend of protein and mRNA levels of PLAG1, which is not caused by affecting the stability or ubiquitination of PLAG1 protein, but by the regulation of PLAG1 at the transcriptional level by its upstream competitive endogenous long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1). Data from 139 HCC patients showed a significant positive correlation between PLAG1 and GPX4 levels in tumor samples, and PLAG1 is instrumental in redox homeostasis by driving the expression of glutathione peroxidase 4 (GPX4), the enzyme that reduces lipid peroxides (LPOs), which further leads to ferroptosis inhibition.ConclusionsFerroptosis is a promising target for cancer therapy, especially for patients resistant to standard chemotherapy or immunotherapy. Our findings indicate that PLAG1 holds therapeutic promise and may enhance the efficacy of sorafenib in treating HCC.

Statement of Retraction: Circular RNA Plasmacytoma Variant Translocation 1 (CircPVT1) knockdown ameliorates hypoxia-induced bladder fibrosis by regulating the miR-203/Suppressor of Cytokine Signaling 3 (SOCS3) signaling axis

Statement of Retraction: Circular RNA Plasmacytoma Variant Translocation 1 (CircPVT1) knockdown ameliorates hypoxia-induced bladder fibrosis by regulating the miR-203/Suppressor of Cytokine Signaling 3 (SOCS3) signaling axis

A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes.

Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. Thus, new genes were identified, potentially influencing the outcome of HSCT.

The Potential of Salivary Biomarkers in Early Detection of Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a formidable global health concern with a dire prognosis, highlighting the critical need for early detection strategies. This systematic review delves into the potential of salivary biomarkers as a non-invasive means for identifying PDAC at its incipient stages. Saliva's proximity to the circulatory system enables the detection of tumor-derived biomolecules, making it an ideal candidate for mass screening. The analysis of three selected studies reveals promising candidates such as Neisseria mucosa, Fusobacterium periodonticum, polyamines, and specific long non-coding RNAs (lncRNAs). Notably, polyamines like spermine show potential in distinguishing PDAC, while lncRNAs HOX transcript antisense RNA (HOTAIR) and plasmacytoma variant translocation 1 (PVT1) exhibit superior sensitivity and specificity compared to traditional serum markers. However, challenges, including small sample sizes and a lack of validation, underscore the need for standardized diagnostic panels and large-scale collaborative studies. Advancements in nanotechnology, machine learning, and ethical considerations are crucial for harnessing the diagnostic potential of saliva. The review emphasizes the imperative for extensive clinical trials to validate salivary biomarkers, ensuring not only diagnostic accuracy but also cost-effectiveness, patient compliance, and long-term benefits in the realm of PDAC screening. Longitudinal studies are recommended to unravel temporal changes in salivary biomarkers, shedding light on disease progression and treatment response.

Analyzing the expression pattern of the noncoding RNAs (HOTAIR, PVT‐1, XIST, H19, and miRNA‐34a) in PBMC samples of patients with COVID‐19, according to the disease severity in Iran during 2022–2023: A cross‐sectional study

AbstractBackground and aimsMicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are well‐known types of noncoding RNAs (ncRNAs), which have been known as the key regulators of gene expression. They can play critical roles in viral infection by regulating the host immune response and interacting with genes in the viral genome. In this regard, ncRNAs can be employed as biomarkers for viral diseases. The current study aimed to evaluate peripheral blood mononuclear cell (PBMC) ncRNAs (lncRNAs‐homeobox C antisense intergenic RNA [HOTAIR], ‐H19, X‐inactive‐specific transcript [XIST], plasmacytoma variant translocation 1 [PVT‐1], and miR‐34a) as diagnostic biomarkers to differentiate severe COVID‐19 cases from mild ones.MethodsCandidate ncRNAs were selected according to previous studies and assessed by real‐time polymerase chain reaction in the PBMC samples of patients with severe coronavirus disease 2019 (COVID‐19) (n = 40), healthy subjects (n = 40), and mild COVID‐19 cases (n = 40). Furthermore, the diagnostic value of the selected ncRNAs was assessed by analyzing the receiver‐operating characteristic (ROC).ResultsThe results demonstrated that the expression pattern of the selected ncRNAs was significantly different between the studied groups. The levels of HOTAIR, XIST, and miR‐34a were remarkably overexpressed in the severe COVID‐19 group in comparison with the mild COVID‐19 group, and in return, the PVT‐1 levels were lower than in the mild COVID‐19 group. Interestingly, the XIST expression level in men with severe COVID‐19 was higher compared to women with mild COVID‐19. ROC results suggested that HOTAIR and PVT‐1 could serve as useful biomarkers for screening mild COVID‐19 from severe COVID‐19.ConclusionsOverall, different expression patterns of the selected ncRNAs and ROC curve results revealed that these factors can contribute to COVID‐19 pathogenicity and can be considered diagnostic markers of COVID‐19 severe outcomes.

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.

Recent Approaches on Molecular Markers, Treatment and Novel Drug Delivery System Used for the Management of Colorectal Cancer: A Comprehensive Review.

Colorectal cancer affects 1 in 25 females and 1 in 24 males, making it the third most frequent cancer with over 6,08,030 deaths worldwide, despite advancements in detection and treatments, including surgery, chemotherapeutics, radiotherapy, and immune therapeutics. Novel potential agents have increased survival in acute and chronic disease conditions, with a higher risk of side effects and cost. However, metastatic disease has an insignificant long-term diagnosis, and significant challenges remain due to last-stage diagnosis and treatment failure. Early detection, survival, and treatment efficacy are all improved by biomarkers. The advancement of cancer biomarkers' molecular pathology and genomics during the last three decades has improved therapy. Clinically useful prognostic biomarkers assist clinical judgment, for example, by predicting the success of EGFR-inhibiting antibodies in the presence of KRAS gene mutations. Few biomarkers are currently used in clinical settings, so further research is still needed. Nanocarriers, with materials like Carbon nanotubes and gold nanoparticles, provide targeted CRC drug delivery and diagnostics. Light-responsive drugs with gold and silica nanoparticles effectively target and destroy CRC cells. We evaluate the potential use of the long non-coding RNA (non-coding RNA) oncogene plasmacytoma variant translocation 1 (PVT1) as a diagnostic, prognostic, and therapeutic biomarker, along with the latest nanotech breakthroughs in CRC diagnosis and treatment.

PVT1 promotes proliferation and macrophage immunosuppressive polarization through STAT1 and CX3CL1 regulation in glioblastoma multiforme.

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). We assessed aberrant PVT1 expression in glioma tissues and its impact on GBM cell growth invitro and invivo. 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. 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 invitro and invivo. 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. 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.

Expression of PVT-1 and miR-29a/29b as reliable biomarkers for liver cirrhosis and their correlation with the inflammatory biomarkers profile.

The liver is a vital organ responsible for numerous metabolic processes, which can be significantly impacted by long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). These ribonucleic acid (RNA) molecules have been shown to play a crucial role in regulating gene expression, and their dysregulation has been implicated in numerous liver disorders. Our study aimed to investigate the diagnostic accuracy of plasmacytoma variant translocation-1 (PVT-1), microRNA-29a/29b (miR-29a/miR-29b), and inflammatory biomarkers [ interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and insulin growth factor-1 (IGF-1)] as diagnostic and prognostic biomarkers for liver cirrhosis. Therefore, understanding the mechanisms by which lncRNAs and miRNAs influence liver metabolism is of paramount importance in developing effective treatments for liver-related diseases. Serum samples were collected from 164 participants, comprising 114 cirrhotic patients with varying grades (35 grade I, 35 grade II, and 44 grade III) and 50 healthy controls. PVT-1 and miR-29a/miR-29b expression was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-PCR), while the serum levels of inflammatory biomarkers were assessed using enzyme-linked immunosorbent assay (ELISA). The study participants exhibited notable differences in PVT-1 and miR-29a/miR-29b expression. ROC analysis revealed excellent discriminative power for PVT-1 and miR-29a/miR-29b in distinguishing cirrhotic patients from healthy controls. This study demonstrates the promising potential of PVT-1 and miR-29a/miR-29b as early diagnostic biomarkers for liver cirrhosis detection, requiring further validation in larger cohorts. Our findings also reinforce the diagnostic value of circulating inflammatory biomarkers (IL-6, TNF-α, TGF-β, and IGF-1) levels for liver cirrhosis screening.

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.

Long non-coding RNA PVT1 (PVT1) affects the expression of CCND1 and promotes doxorubicin resistance in osteosarcoma cells

BackgroundAcquired 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. MethodsThe 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. ResultsIn 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. ConclusionThe 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.

Long noncoding RNA plasmacytoma variant translocation1 is overexpressed in cutaneous squamouscell carcinoma and exon 2 is critical for itsoncogenicity.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common and fastest increasing forms of cancer worldwide with metastatic potential. Long noncoding RNAs (lncRNAs) are a group of RNA molecules with essential regulatory functions in both physiological and pathological processes. To investigate the function and mode of action of lncRNA plasmacytoma variant translocation 1 (PVT1) in cSCC. Quantitative reverse transcriptase polymerase chain reaction and single-molecule in situ hybridization were used to quantify the expression level of PVT1 in normal skin, premalignant skin lesions, actinic keratosis (AK) and primary and metastatic cSCCs. The function of PVT1 in cSCC was investigated both in vivo (tumour xenografts) and in vitro (competitive cell growth assay, 5-ethynyl-2'-deoxyuridine incorporation assay, colony formation assay and tumour spheroid formation assay) upon CRISPR-Cas9-mediated knockout of the entire PVT1 locus, the knockout of exon 2 of PVT1, and locked nucleic acid (LNA) gapmer-mediated PVT1 knockdown. RNA sequencing analysis was conducted to identify genes and processes regulated by PVT1. We identified PVT1 as a lncRNA upregulated in cSCC in situ and cSCC, associated with the malignant phenotype of cSCC. We showed that the expression of PVT1 in cSCC was regulated by MYC. Both CRISPR-Cas9 deletion of the entire PVT1 locus and LNA gapmer-mediated knockdown of PVT1 transcript impaired the malignant behaviour of cSCC cells, suggesting that PVT1 is an oncogenic transcript in cSCC. Furthermore, knockout of PVT1 exon 2 inhibited cSCC tumour growth both in vivo and in vitro, demonstrating that exon 2 is a critical element for the oncogenic role of PVT1. Mechanistically, we showed that PVT1 was localized in the cell nucleus and its deletion resulted in cellular senescence, increased cyclin-dependent kinase inhibitor 1 (p21/CDKN1A) expression and cell cycle arrest. Our study revealed a previously unrecognized role for exon 2 of PVT1 in its oncogenic role and that PVT1 suppresses cellular senescence in cSCC. PVT1 may be a potential biomarker and therapeutic target in cSCC.

LncRNA PVT1 induces apoptosis and inflammatory response of bronchial epithelial cells by regulating miR-30b-5p/BCL2L11 axis in COPD

BackgroundChronic 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.MethodsCigarette 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.ResultsPVT1 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.ConclusionPVT1 enhances apoptosis and inflammation of 16HBE cells under CSE stimulation by modulating miR-30b-5p/BCL2L11 axis.

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.

Proliferation-promoting roles of linear and circular PVT1 are independent of their ability to bind miRNAs in B-cell lymphoma

Plasmacytoma Variant Translocation 1 (PVT1) is a long non-coding RNA located at 8q24.21 immediately downstream of MYC. Both the linear and circular PVT1 transcripts contribute to cancer pathogenesis by binding microRNAs. However, little is known about their roles in B-cell lymphoma. Here we studied their expression patterns, role in growth, and ability to bind miRNAs in B-cell lymphoma. Linear PVT1 transcripts were downregulated in B-cell cell lymphoma lines compared to germinal center B cells, while circPVT1 levels were increased. Two Hodgkin lymphoma cell lines had a homozygous deletion including the 5′ region of the PVT1 locus, resulting in a complete lack of circPVT1 and 5′ linear PVT1 transcripts. Inhibition of both linear and circular PVT1 decreased growth of Burkitt lymphoma, while the effects on Hodgkin lymphoma and diffuse large B cell lymphoma were less pronounced. Overexpression of circPVT1 promoted growth of B-cell lymphoma lacking or having low endogenous circPVT1 levels. Contrary to other types of cancer, linear and circular PVT1 transcripts did not interact with miRNAs in B-cell lymphoma. Overall, we showed an opposite expression pattern of linear and circular PVT1 in B-cell lymphoma. Their effect on growth was independent of their ability to bind miRNAs.

PVT1 interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma.

Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.

VirhostlncR: A comprehensive database to explore lncRNAs and their targets in viral infections

Long non-coding-RNAs (lncRNAs) are an expanding set of cis-/trans-regulatory RNA genes that outnumber the protein-coding genes. Although being increasingly discovered, the functional role of the majority of lncRNAs in diverse biological conditions is undefined. Increasing evidence supports the critical role of lncRNAs in the emergence, regulation, and progression of various viral infections including influenza, hepatitis, coronavirus, and human immunodeficiency virus. Hence, the identification of signature lncRNAs would facilitate focused analysis of their functional roles accounting for their targets and regulatory mechanisms associated with infections. Towards this, we compiled 2803 lncRNAs identified to be modulated by 33 viral strains in various mammalian cell types and are provided through the resource named VirhostlncR (http://ciods.in/VirhostlncR/). The information on each of the viral strains, their multiplicity of infection, duration of infection, host cell name and cell types, fold change of lncRNA expression, and their specific identification methods are integrated into VirhostlncR. Based on the current datasets, we report 150 lncRNAs including differentiation antagonizing non-protein coding RNA (DANCR), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), maternally expressed gene 3 (MEG3), nuclear paraspeckle assembly transcript 1 (NEAT1), and plasmacytoma variant translocation 1 (PVT1) to be perturbed by two or more viruses. Analysis of viral protein interactions with human transcription factors (TFs) or TF-containing protein complexes identified that distinct viruses can transcriptionally regulate many of these lncRNAs through multiple protein complexes. Together, we believe that the current dataset will enable priority selection of lncRNAs for identification of their targets and serve as an effective platform for the analysis of noncoding RNA-mediated regulations in viral infections.

Abstract A064: Prediction of positive prostate biopsy is significantly improved in Black and Hispanic men when serum PVT1 exon 9 copy number is combined with serum prostate specific antigen

Abstract Background Men of African ancestry (moAA) experience the highest incidence and mortality rates of prostate Cancer (PCa) in the United States, where 1 in 8 men are expected to be diagnosed with the disease in their lifetime. Yet, most biomarkers used in PCa screening today, which are based on prostate specific antigen (PSA), are developed and validated in predominantly White populations with weak or nonexistent validation in moAA, making moAA more likely to be subjected to unnecessary prostate biopsies. To reduce this disparity in PCa detection and management, there is a critical need for new biomarkers that target the unique genetic make-up of moAA. We recently showed that plasmacytoma variant translocation 1 (PVT1), exons 4A, 4B, and 9 are overexpressed in the prostate tissues and detected in higher copy numbers in serum of moAA with PCa. In this study, we investigated the predictive power of these potential biomarkers in detecting PCa across different racial populations. Methodology Forty serum samples from White, Hispanic, and Black men, 50 percent of whom had PCa, were analyzed to obtain copy numbers for PVT1 exons 4A, 4B, and 9. Seven logistic regression models were developed to predict PCa using single biomarkers, all pairwise combinations of biomarkers and all three biomarkers. The median area under the receiver operator characteristic curve (AUC) was used to measure the predictive accuracy of each model after a repeated, stratified k-fold cross validation. Model accuracy was first evaluated using data from all races and then for just the Black and Hispanic subpopulation. Our best performing models were compared with PSA as a predictor of PCa. We also evaluated the predictive accuracy of composite models that combined our biomarkers with PSA. Results In predicting PCa for all races, our model with only PVT1 exon 9 achieved the highest median AUC of 0.71, which was better than the AUC of 0.63 obtained with just PSA. When PSA and PVT1 exon 9 were combined, the median AUC increased to 0.75. Combining all three biomarkers with PSA increased the median AUC to 0.813. For the Black and Hispanic subpopulation, PVT1 exon 9 achieved the highest AUC of 0.92 which was significantly higher than the median AUC of 0.63 achieved with PSA. No significant change in AUC was observed when the PVT1 biomarkers were combined with PSA. Conclusion Our results show that PVT1 exon 9 is more accurate than PSA in predicting PCa, achieving near perfect accuracy within the Black and Hispanic subpopulation. Whereas combining PSA with PVT1 biomarkers improved the performance of PSA for all races, no significant improvement in PSA’s performance was observed in Black and Hispanic subpopulations. Thus, PVT1 exon 9 may hold the key to reducing disparity in PCa detection among moAA while improving the predictive accuracy of PSA for the general population Citation Format: Emmanuel Owusu Asante-Asamani, Dinuka Sewandi De Silva, Gargi Pal, Michael Liss, Robin Leach, Olorunseun Ogunwobi. Prediction of positive prostate biopsy is significantly improved in Black and Hispanic men when serum PVT1 exon 9 copy number is combined with serum prostate specific antigen [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A064.

Abstract A065: Serum PVT1 exons 4A and 4B copy numbers are better predictors of high-grade prostate cancer in Black and Hispanic men than serum prostate specific antigen

Abstract Background Men of African ancestry (moAA) experience the highest incidence and mortality rates of prostate Cancer (PCa) in the United States, where 1 in 8 men are expected to be diagnosed with the disease in their lifetime. Yet, most biomarkers used in PCa screening today, which are based on prostate specific antigen (PSA), are developed and validated in predominantly White populations with weak or nonexistent validation in moAA, making moAA more likely to be subjected to unnecessary prostate biopsies. To reduce this disparity in PCa detection and management, there is a critical need for new biomarkers with demonstrated usefulness in moAA. We recently showed that plasmacytoma variant translocation 1 (PVT1), exons 4A, 4B, and 9 are overexpressed in the prostate tissues and detected in higher copy numbers in serum of moAA with PCa. In this study, we investigated the predictive power of these potential biomarkers in detecting high-grade PCa across different racial populations. Methodology Forty serum samples from White, Hispanic, and Black men, 50% of whom had PCa with 25% showing high-grade PCa, were analyzed to obtain copy numbers for PVT1 exons 4A, 4B, and 9. Seven logistic regression models were developed to predict PCa using individual PTV1 biomarkers, all pairwise combinations of biomarkers and all three biomarkers. The median area under the receiver operator characteristic curve (AUC) was used to measure the predictive accuracy of each model after a repeated, stratified k-fold cross validation. Model accuracy was first evaluated using data from all races and then for just the Black and Hispanic subpopulation. Our best performing models were compared with PSA as a predictor of PCa. We also evaluated the predictive accuracy of composite models that combined our biomarkers with PSA. Results In predicting high-grade PCa for all races, PSA had a median AUC of 0.58. All our PVT1 biomarkers had an AUC greater than 0.64, which was better than PSA. When PSA and PVT1 exon 4B were combined, the median AUC of PSA increased to 0.67, other PTV1 biomarkers did not improve the AUC of PSA. For the Black and Hispanic subpopulation, PVT1 exon 4A achieved the highest median AUC of 0.92 which was significantly higher than the median AUC of 0.33 achieved with PSA. The model with Exon 4A and Exon 4B as well as all three biomarkers achieved perfect discrimination (AUC of 1.0). We were also able to obtain perfect discrimination when PVT1 exon 4A was combined with PSA (AUC: 1.0). Conclusion Our results show that PVT1 exon 4A is more accurate than PSA in predicting high-grade PCa in Black and Hispanic subpopulations, achieving perfect discrimination when combined with PSA. Significant improvement in PSA’s predictability is observed in all races when combined with PTV1 exon 4B. Thus, PVT1 exon 4A and PVT1 exon 4B may hold the key to reducing disparity in high-grade PCa detection among moAA while improving the predictive accuracy of PSA for the general population. Citation Format: Emmanuel Owusu Asante-Asamani, Dinuka S.H. Sewandi De Silva, Gargi Pal, Michael Liss, Robin Leach, Olorunseun O. Ogunwobi. Serum PVT1 exons 4A and 4B copy numbers are better predictors of high-grade prostate cancer in Black and Hispanic men than serum prostate specific antigen [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A065.

PVT1 alleviates hypoxia-induced endothelial apoptosis by enhancing autophagy via the miR-15b-5p/ATG14 and miR-424-5p/ATG14 axis

Endothelial dysfunction plays a crucial role in the pathogenesis of vascular disease. Long noncoding RNA (lncRNA) and microRNA (miRNA) play important roles in various cellular processes and are involved in several vascular endothelial cells (VECs) biological processes, including cell growth, migration, autophagy, and apoptosis. The functions of plasmacytoma variant translocation 1 (PVT1) in VECs have been progressively investigated in recent years, mainly with regard to proliferation and migration of endothelial cells (ECs). However, the mechanism underlying the regulation of autophagy and apoptosis in human umbilical vein endothelial cells (HUVEC) by PVT1 remains unclear. The present study showed that PVT1 knockdown accelerated apoptosis induced by oxygen and glucose deprivation (OGD) through suppression of cellular autophagy. Bioinformatic prediction of PVT1 target miRNAs revealed that PVT1 interacts with miR-15b-5p and miR-424-5p. The study further showed that miR-15b-5p and miR-424-5p inhibit the functions of autophagy related 14 (ATG14) and suppress cellular autophagy. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy by competitive binding, which down-regulates apoptosis. The results showed that PVT1 can function as a competing endogenous RNA (ceRNA) of miR-15b-5p and miR-424-5p and promote cellular autophagy through competitive binding, which down-regulates apoptosis. The study provides insight into a novel therapeutic target that may be explored in the future for the treatment of cardiovascular disease.