Plasmacytoma Variant Translocation Research Articles

PVT1 promotes resistance to 5-FU in colon cancer via the miR-486-5p/CDK4 axis.

Drug resistance in tumors is a major issue, limiting the curative efficacy of currently available cancer chemotherapeutics. 5-Fluorouracil (5-FU) is a commonly applied therapeutic drug in colon cancer patient regimens; however, the majority of patients develop resistance to 5-FU in the later stages of the disease, rendering this chemotherapy ineffective. Drug resistance is the main factor underlying the poor prognosis of patients with colon cancer. In recent years, a number of studies have confirmed that long non-coding (lnc)RNAs may play vital roles in tumor resistance. In the present study, the Gene Expression Omnibus (GEO) and lncRNADisease2 databases were screened for colon cancer-associated expression patterns of lncRNA plasmacytoma variant translocation 1 (PVT1). Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect changes in PVT1 expression in resistant cell lines, and a Cell Counting Kit-8 (CCK-8) assay kit was used to assess the effects of PVT1 knockdown on the half maximal inhibitory concentrations of parental and 5-FU-resistant HCT116 cells. Subsequently, CCK-8, clone formation, and flow cytometric assays were performed to investigate the effects of PVT1 knockdown on the sensitivity of HCT116-5FU-resistant cells to 5-FU. Dual-luciferase assay, RNA pull-down and RNA immunoprecipitation assays verified the interactive regulation of PVT1, miR-486-5p and cyclin dependent kinase 4 (CDK4). PVT1 was highly expressed in HCT116-5FU-resistant cells, as compared to its expression in HCT116 parental cells. PVT1 knockdown significantly reduced the resistance of HCT116-5FU-resistant cells to 5-FU. In addition, PVT1 upregulated CDK4 expression by adsorbing miR-486-5p; however, CDK4 overexpression restored the effects of miR-486-5p inhibition on HCT116-5-FU-resistant cells. Additionally, PVT1 knockdown partially rescued CDK4 overexpression in HCT116-5-FU-resistant cells. On the whole, the findings of the present study suggest that PVT1 promotes the resistance of colon cancer cells to 5-FU by regulating the miR-486-5p/CDK4 axis. Therefore, PVT1 may prove to be a potential target for counteracting resistance to 5-FU in colon cancer therapy.

Long noncoding RNA PVT1 accelerates the growth of placental trophoblasts in preeclampsia through the microRNA‐24‐3p/HSD11B2 axis

Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) is essential for the maintenance of normal functions of trophoblasts in preeclampsia (PE).This study aims to decipher the concrete mechanism of PVT1 with the microRNA-24-3p/Type-2 11β-hydroxysteroid dehydrogenase (miR-24-3p/HSD11B2) axis in PE. PVT1, miR-24-3p, and HSD11B2 expression levels in normal placental tissues and PE placental tissues were defined. HTR-8/SVneo cells were transfected to determine the effects of PVT1, miR-24-3p, and HSD11B2 on the growth of HTR-8/SVneo cells. The relationships among PVT1/miR-24-3p/HSD11B2 in HTR-8/SVneo cells were identified. PVT1 and HSD11B2 were downregulated, while miR-24-3p was upregulated in the placenta of PE. Upregulated/downregulated PVT1 promoted/impeded the growth of human placental trophoblast (HTR-8/SVneo) cells in PE. Restored/knocked down miR-24-3p impeded/enhanced the growth of HTR-8/SVneo cells in PE. PVT1 inhibited miR-24-3p to mediate HSD11B2. PVT1 sponges miR-24-3p to regulate HSD11B2; thereby, the growth of placental trophoblasts is promoted in PE.

Abstract 1555: circPVT1 and linear PVT1 isoforms regulate cell growth, metabolic and DNA damage response related gene signatures in acute myeloid leukemia

Abstract Non-coding (nc)RNAs, including circular (circ)RNAs, contribute to tumor development and progression. Several ncRNAs were shown to affect the onset, prognosis, and treatment of acute myeloid leukemia (AML) in the past years. The human Plasmacytoma Variant Translocation 1 (PVT1) gene maps on the long arm of chromosome 8 (8q24), in the same genomic region hosting MYC and encoding for 83 linear (PVT1, lncipedia.org) and 26 high-confidence circular isoforms (circPVT1, www.circbase.org). The most common isoform of circPVT1 is a product of back-splicing of 410 nt and contains the whole exon 2 of PVT1 in a closed loop-like structure (hsa_circ_0001821). The study aims to investigate the role of PVT1 isoforms and circPVT1 in AML. Firstly, we focused on the various PVT1 isoforms and their differential expression in leukemia. Fourteen out of the 83 linear isoforms are expressed in the hematopoietic tissues (lymph node and white blood cells, www.noncode.org), and 6 of them were detectable in AML cell lines, including the t(8;21) KASUMI-1 and the NPM1-mutated OCI-AML3 models, together with circPVT1. We designed two antisense-oligonucleotides (ASOs), mapping on common exonic region and targeting the linear isoforms expressed in OCI-AML3 and KASUMI-1 cells, and one ASO spanning the junction region of circPVT1. ASOs-mediated knockdown (KD) showed a relevant decrease of PVT1 signals, especially by ASO combination, and circPVT1 level using the specific ASO in both cell lines, under normoxia and hypoxia (1% O2). The downregulation led to a significant decrease in cell growth, but, interestingly, only circPVT1-KD induced apoptosis under both conditions in OCI-AML3. To further investigate the biological consequences of circPVT1-KD, we performed RNAseq assays. Data analysis was performed by pseudo alignment of paired-end reads to the human transcriptome, then counted with the Kallisto tool. Differential expression analysis of single isoforms was performed with the Sleuth tool on normalized transcript per million. We identified a core of 644 and 838 commonly regulated genes by circPVT1 in both cell lines under normoxia and hypoxia, respectively. Pathway analysis (performed by EnrichR) revealed that these genes are involved not only in the RNA regulatory pathways, as expected according to circRNA functions, but also in metabolic (e.g., KDM3A, GPI, NFKBA, RBM3, XBP1) and DNA damage response (e.g., PIDD1, MUC1, BCLAF1, BABAM2) pathways, opening a new scenario for synthetic lethality approaches. In conclusion, our findings show that silencing of circPVT1 or the predominantly expressed PVT1 isoforms dampens leukemia cell growth, indicating a role in AML pathogenesis, and suggest that targeting them may have therapeutic potentials in AML. Citation Format: Martina Ghetti, Antonella Padella, Eugenio Fonzi, Lorenzo Ledda, Andrea Ghelli Lusernadi Rorà, Matteo Paganelli, Doron Tolomeo, Clelia Tiziana Storlazzi, Giovanni Martinelli, Giorgia Simonetti. circPVT1 and linear PVT1 isoforms regulate cell growth, metabolic and DNA damage response related gene signatures in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1555.

CircPVT1 facilitates the progression of oral squamous cell carcinoma by regulating miR-143-3p/SLC7A11 axis through MAPK signaling pathway.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor occurring in the oral cavity. Circular RNAs (circRNAs) play a crucial regulatory role in many cancers. This study aimed to investigate the function of circRNA plasmacytoma variant translocation 1 (PVT1) (circPVT1) in OSCC and its potential mechanism. The levels of circPVT1, solute carrier family 7 member 11 (SLC7A11), and microRNA-143-3p (miR-143-3p) were examined by quantitative real-time PCR (qRT-PCR) or western blot assay. Cell proliferation, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay, flow cytometry, and transwell assay. The levels of apoptosis and proliferation-related proteins were examined by western blot. The targeting relationship between miR-143-3p and circPVT1 or SLC7A11 was verified by dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. The levels of mitogen-activated protein kinase (MAPK) pathway-related proteins were measured by western blot. Xenograft assay was used to assess tumor growth in vivo. CircPVT1 and SLC7A11 were upregulated, while miR-143-3p was downregulated in OSCC tissues and cells. Silencing of circPVT1 or SLC7A11 suppressed proliferation, migration, and invasion and promoted apoptosis in OSCC cells. CircPVT1 upregulated SLC7A11 expression via sponging miR-143-3p. SLC7A11 upregulation alleviated the effect of circPVT1 knockdown on OSCC cell progression. Besides, circPVT1 modulated MAPK signaling pathway by regulating miR-143-3p. Moreover, circPVT1 knockdown inhibited tumor growth in vivo. Knockdown of circPVT1 impeded OSCC progression via the miR-143-3p/SLC7A11 axis through MAPK signaling pathway.

LncRNA PVT1 Promotes Cell Proliferation, Invasion, and Migration and Inhibits Cell Apoptosis by Phosphorylating YAP.

Gastric cancer (GC) as a serious global health problem is a threat to human longevity. Plasmacytoma variant translocation 1 (PVT1) participates in the formation and progression of various cancers, including GC. The aim of this study is to investigate the mechanism underlying the functions of PVT1 and explore a novel target for the diagnosis and treatment of GC. Analysis of the TCGA dataset using the R software identified that the lncRNA PVT1 was greatly upregulated in GC tissues. Twenty pairs of GC and adjacent normal tissues were acquired from patients with GC, and the expression of PVT1 was evaluated using RT-qPCR. Furthermore, PVT1 expression was knocked down in GC cells using siRNA, and the GC cells were divided into control, negative control (NC), and siRNA groups. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) and colony formation assays, whereas cell migration and invasion ability were investigated through wound healing and Transwell assays. Moreover, Western blotting was used to analyze the expression of Yes-associated protein (YAP) and epithelial-to-mesenchymal transition (EMT) proteins. We also found that PVT1 and YAP expressions were upregulated in the GC tissues compared with those in the adjacent nontumor tissues. Knockdown of PVT1 was found to inhibit the proliferation, invasion, and migration and promote apoptosis of GC cells. Furthermore, knockdown of PVT1 downregulated YAP and promoted phosphorylation of YAP, suggesting that PVT1 exerts actions on GC cells by targeting YAP and inhibits cell apoptosis in vitro. The EMT process was also inhibited by the knockdown of PVT1. In summary, lncRNA PVT1 facilitated cell proliferation, invasion, and migration and suppressed cell apoptosis by targeting YAP. This study suggests that the expressions of PVT1 and YAP could be used for the early detection of GC and the occurrence and development of GC could be inhibited by interfering the interaction of PVT1 and YAP, which will provide new insights for the diagnosis, treatment, and prognosis of GC.

Long non-coding RNA plasmacytoma variant translocation 1 and growth arrest specific 5 regulate each other in osteoarthritis to regulate the apoptosis of chondrocytes

ABSTRACT Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and growth arrest specific 5 (GAS5) have opposite functions in the apoptosis of chondrocytes, which are involved in the pathogenesis of osteoarthritis (OA). The opposite roles of PVT1 and GAS5 in OA may indicate the existence of crosstalk between them in OA. This study aimed to explore the possible interaction between PVT1 and GAS5 in OA. Accumulation of PVT1 and GAS5 in OA and control synovial fluid samples was measured by RT-qPCR. The interaction between PVT1 and GAS5 in chondrocytes was explored by overexpression experiments. Dual-luciferase reporter assay was performed to analyze the binding of PVT1 and GAS5 to each other’s promoter regions. Regulatory roles of PVT1 and GAS5 in the apoptosis of chondrocytes were studied with cell apoptosis assay. PVT1 was upregulated in OA, and GAS5 was downregulated in OA. An inverse correlation between PVT1 and GAS5 was observed across OA samples. Under lipopolysaccharides (LPS) treatment, PVT1 was upregulated and GAS5 was downregulated. Interestingly, PVT1 and GAS5 overexpression downregulated each other in chondrocytes. Cell apoptosis analysis showed that PVT1 overexpression promoted cell apoptosis, while GAS5 overexpression suppressed cell apoptosis induced by LPS. Co-transfection of PVT1 and GAS5 failed to significantly affect cell apoptosis. PVT1 and GAS5 directly bound to each other’s promoter regions. Our study characterized the interaction between PVT1 and GAS5 in OA. Their interaction regulated the apoptosis of chondrocytes, which play a critical role in OA. PVT1 and GAS5 may form a negative feedback loop in OA.

Serum Long Non-Coding RNAs in Diabetic Kidney Disease

Background: Diabetic kidney disease (DKD) afflicts almost 40% of type 2 diabetes mellitus (T2DM) patients and may progress to end-stage renal disease despite multifactorial management. Urinary albumin/creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are not sufficiently sensitive or specific for early diagnosis or recognition of patients at higher risk of cardiorenal complications. Long non-coding RNAs (lncRNAs) emerged as key regulators of major DKD signaling pathways. Their potential role as novel biomarkers or therapeutic targets in DKD remains to be established. Methods: We studied 4 groups of 25 adults each. G1, 2, 3 had T2DM and normal, moderately-increased, and severely-increased UACR, respectively. G4 were healthy controls. Participants underwent clinical assessment and analysis of blood picture, fasting serum glucose, glycated hemoglobin, lipid profile, hepatic transaminases, albumin, urea, and creatinine. By real-time quantitative polymerase chain reaction, we assessed relative serum expression levels of the lncRNAs plasmacytoma variant translocation-1 gene (PVT1), metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), and cancer susceptibility candid-2 gene (CASC2). Results: Serum PVT1 was significantly higher in diabetic patients compared with controls, and significantly higher in G2 compared with the other patients’ groups. Serum MALAT1 and CASC2 showed no statistically significant association with the occurrence of T2DM, DKD, or other major diabetic complications. Increased serum creatinine was the only significant predictor of increased UACR. Conclusions: Increased serum PVT1 is a reliable early biomarker of DKD progression. It may provide a plausible therapeutic approach. The involvement of MALAT1 and CASC2 in DKD pathogenesis is less established. Further large-scale prospective studies are warranted.

Long noncoding RNA PVT1 regulates the proliferation and apoptosis of ARPE-19 cells in vitro via the miR-1301-3p/KLF7 axis

ABSTRACT Diabetic retinopathy (DR) as a frequent diabetic microvascular complication shows signs in one-third of diabetic patients. Long non-coding RNAs (lncRNAs) have drawn increasing attention because of their regulatory roles in DR. LncRNA plasmacytoma variant translocation 1 (PVT1) is documented to be upregulated in diabetes-related diseases, while its effects in DR remains unexplored. ARPE-19 cells under the treatment of high-glucose (HG) were used as DR cell models. The gene expression in ARPE-19 cells was examined using RT-qPCR. The viability and apoptosis of ARPE-19 cells were determined by MTT and TUNEL assays. The levels of inflammation-associated proteins or mRNA were measured using western blot. Luciferase reporter assay and RNA pull down assay were conducted for the exploration of the underlying mechanism of PVT1. PVT1 was revealed to be upregulated in DR cell models. Silencing of PVT1 promoted the viability and inhibited apoptosis of HG-stimulated ARPE-19 cells. The results revealed that PVT1 can bind with miR-1301-3p. PVT1 negatively modulated miR-1301-3p expression. Additionally, KLF7 was targeted by miR-1301-3p. PVT1 upregulated KLF7 expression by binding with miR-1301-3p. The silenced PVT1-mediated influence on cell viability and cell apoptosis was rescued by overexpression of KLF7. PVT1 suppresses proliferation and promotes apoptosis of ARPE-19 cells treated with HG in vitro by binding with miR-1301-3p to upregulate KLF7.

Long noncoding RNA PVT1 promotes chondrocyte extracellular matrix degradation by acting as a sponge for miR-140 in IL-1\u03b2-stimulated chondrocytes

BackgroundOsteoarthritis (OA) is a common degenerative joint disease, and chondrocyte extracellular matrix (ECM) degradation is one vital pathological feature of OA. Long noncoding RNA (lncRNA), a new kind of gene regulator, plays an important role in pathogenesis of many diseases like OA. Recent studies have confirmed that lncRNA plasmacytoma variant translocation 1 (PVT1) expression was upregulated in OA patients; however, its effect on ECM degradation remained unknown.MethodsCartilage tissue samples were obtained from 6 OA patients admitted in Guangdong Second Traditional Chinese Medicine Hospital. Chondrocytes were isolated and cultured from the collected cartilage tissue. Plasmid construction, RNA interference, cell transfection, fluorescence in situ hybridization (FISH), and pull-down assay were carried out during the research.ResultsIn this study, PVT1 expression was significantly increased in chondrocytes stimulated by interleukin-1β (IL-1β). In addition, inhibition of PVT1 significantly downregulated the increased expressions of ADAM metallopeptidase with thrombospondin type 1 motif-5 (ADAMTS-5) and matrix metalloproteinase-13 (MMP-13) induced by IL-1β. Further investigation revealed that PVT1 was an endogenous sponge RNA, which directly bound to miR-140 and inhibited miR-140 expression.ConclusionTo sum up, this study showed that PVT1 promoted expressions of ADAMTS-5 and MMP-13 as a competing endogenous RNA (ceRNA) of miR-140 in OA, which eventually led to aggravation of ECM degradation, thus providing a new and promising strategy for the treatment of OA.

Plasmacytoma variant translocation 1 stabilized by EIF4A3 promoted malignant biological behaviors of lung adenocarcinoma by generating circular RNA LMNB2

ABSTRACT Increasing evidence suggests that plasmacytoma variant translocation 1 (PVT1) plays a vital role in the development of multiple tumors including lung adenocarcinoma (LUAD). Eukaryotic initiation factor 4A-3 (EIF4A3) is considered a key factor in human cancers. However, the role and potential mechanism of PVT1 combined with EIF4A3 in LUAD remain unclear. This study investigated the effects and regulatory mechanisms of PVT1, EIF4A3, and circLMNB2 on the growth, migration, invasion, and epithelial-mesenchymal transition (EMT) of LUAD cells (H1299 and HCC827 cells) The expression level, diagnostic value and prognostic significance of PVT1, EIF4A3, and circLMNB2 were assessed, and enrichment analysis was performed using R package. Rescue experiments and a xenograft model were used to validate the PVT1/EIF4A3/circLMNB2 axis in LUAD. PVT1 and EIF4A3 were upregulated and indicated poor prognosis in LUAD. Knockdown of PVT1 and EIF4A3 suppressed LUAD cell proliferation, migration, invasion, and EMT. Mechanistically, PVT1 was stabilized by EIF4A3. PVT1 could recruit EIF4A3 to promote circLMNB2 expression. Rescue experiments indicated that circLMNB2 overexpression could reverse the reduced behavior caused by PVT1 or EIF4A3 knockdown. Enrichment analysis showed that PVT1/EIF4A3/circLMNB2 may regulate LUAD development by participating in ribosome biogenesis and spliceosome formation. Our findings demonstrate that PVT1/EIF4A3/circLMNB2 enhances the malignant behaviors of LUAD cells, providing a novel perspective for the clinical treatment of LUAD.

LncRNA-targeting bio-scaffold mediates triple immune effects for postoperative colorectal cancer immunotherapy

Colorectal cancer (CRC) recurrence after surgical resection results in poor clinical outcomes. Long noncoding RNAs (lncRNAs) are emerging new targets for mediating tumorigenesis and immunosuppression within tumor microenvironment. We develop a bio-scaffold encapsulating lncRNA-targeting biomimetic nanosystems for mediating triple immune effects against postoperative CRC recurrence. Liposome (termed as “D”)-decorated CRC cells’ membrane (CM) envelops a plasmid encoding a short hair-pinned RNA (shRNA) against plasmacytoma variant translocation 1 (Pvt1), forming the shPvt1-CM-D nanosystem. This nanosystem and the chemodrug Oxaliplatin (Oxa) are embedded in a hyaluronic acid and alginate-based bio-scaffold for postoperative implantation. (1) ShPvt1-CM-D-mediated Pvt1 knockdown strengthens Oxa-induced immunogenic cell death (ICD). (2) Such tumor antigens released from enhanced ICD and the CM from shPvt1-CM-D act as dual vaccines of dendritic cells. (3) Pvt1 knockdown by shPvt1-CM-D within granulocytic myeloid-derived suppressor cells (G-MDSCs) ameliorates G-MDSC-mediated immunosuppression. The nanosystem-carrying bio-scaffold significantly suppresses perioperative CRC local recurrence by 97.8% with survival rate (SR) of 62.5%. The bio-scaffold generates robust immune memory responses for completely suppressing tumor ectopic rechallenging and metachronous metastasis (SR: 100%). Additionally, the bio-scaffold reduces synchronously distant metastasis by 70.8%. This work presents a potent nanotechnology-facilitated lncRNA-targeting immunotherapy for postoperative CRC treatments.

Targeting long non-coding RNA PVT1/TGF-β/Smad by p53 prevents glioma progression

ABSTRACT Glioma is a primary intracranial malignant tumor with poor prognosis, and its pathogenesis is unclear. This study discussed the impact of p53/lncRNA plasmacytoma variant translocation 1 (lncRNA PVT1)/transforming growth factor beta (TGF-β)/Smad axis on the biological characteristics of glioma. Glioma and normal tissues were collected, in which relative lncRNA PVT1 and p53 expression was assessed. Pearson’s analysis was adopted for the correlation analysis between lncRNA PVT1 and p53. Short interfering RNA (siRNA) against lncRNA PVT1 (siRNA-PVT1), siRNA-p53 or both was transfected into the glioma cells to evaluate effects of lncRNA PVT1 and p53 on cell proliferation, migration, invasion, and apoptosis. Mouse xenograft model of glioma was established to verify function of lncRNA PVT1 and p53 in vivo. Relationship among p53, lncRNA PVT1 and TGF-β/Smad was predicted and confirmed. Glioma tissues and cells showed downregulated p53 expression and increased lncRNA PVT1 expression. An adverse relationship was noted between p53 expression and lncRNA PVT1 expression. p53 was shown to be enriched in the lncRNA PVT1 promoter region and resulted in its suppression. p53 inhibited glioma cell proliferation, migration, and invasion, and induced apoptosis as well as arrested tumor growth by downregulating lncRNA PVT1. LncRNA PVT1was found to bind to TGF-β and activate TGF-β/Smad pathway, promoting progression of glioma. Consequently, p53 exerts anti-oncogenic function on glioma development by suppressing lncRNA PVT1 and subsequently inactivating TGF-β/Smad pathway.

Aberrant expression of long non-coding RNA PVT1 in allergic rhinitis children: Correlation with disease risk, symptoms, and Th1/Th2 imbalance.

BackgroundLong non‐coding RNA plasmacytoma variant translocation 1 (lnc‐PVT1) exacerbates inflammation and induces T helper (Th) 1/Th2 imbalance in allergic diseases, but its clinical role in allergic rhinitis (AR) remains unclear. Hence, we conducted this study to compare lnc‐PVT1 expression among AR children, disease controls (DCs), and health controls (HCs), aiming to investigate its clinical application in AR children.MethodsSixty AR children, 30 DCs, and 30 HCs were enrolled in the study, and then, their lnc‐PVT1 expression in peripheral blood mononuclear cell was detected. Serum interferon‐gamma (IFN‐γ), interleukin 10 (IL‐10), Th1, and Th2 cells in AR children were also analyzed. Besides, lnc‐PVT1 was also detected at Week (W)4 after treatment in AR patients.ResultsLnc‐PVT1 was upregulated in AR children compared with DCs and HCs (both p < 0.001). Lnc‐PVT1 was positively related to nasal rhinorrhea score, itching score, congestion score, and total nasal symptom score (TNSS) in AR children (all p < 0.050), instead of sneezing score (p = 0.115). Lnc‐PVT1 negatively associated with Th1 cells in AR children (p = 0.028) also exhibited a negative correlation trend with IFN‐γ (but without statistical significance) (p = 0.065). Differently, lnc‐PVT1 was positively related to Th2 cells (p = 0.012) and IL‐10 (p = 0.021) in AR children. Besides, lnc‐PVT1 and TNSS were reduced at W4 after treatment in AR children (both p < 0.001); notably, lnc‐PVT1 expression decline was correlated with TNSS decline during treatment (p = 0.013).ConclusionLnc‐PVT1 works as a biomarker, whose aberrant expression is related to disease severity, Th1/Th2 imbalance, and its decrement can reflect treatment outcome in AR children.

LncRNA PVT1 contributes to invasion and doxorubicin resistance of bladder cancer cells through promoting MDM2 expression and AURKB-mediated p53 ubiquitination.

In most bladder cancer (BC) patients, cancer cells will eventually develop chemical resistance causing increased mortality. This study aimed to explore the mechanism of lncRNA plasmacytoma variant translocation 1 (PVT1) in regulating doxorubicin (ADM) resistance of BC cells. We observed that PVT1 expression was upregulated in ADM-resistant BC cells compared with ADM-sensitive BC cells. Downregulation of PVT1 suppressed ADM-resistant BC cell proliferation and invasion, promoted apoptosis, and increased sensitivity to ADM, while PVT1 overexpression promoted ADM-sensitive BC cell growth and their resistance to ADM. Further study uncovered that PVT1 could interact with and promote mouse double minute 2 (MDM2) expression, and upregulated MDM2-mediated Aurora kinase B (AURKB). Furthermore, Nutlin-3, an inhibitor of MDM2, could counteract the promotive effects of PVT1 overexpression on ADM resistance of ADM-sensitive BC cell, the expression of multidrug-resistance-related proteins, and the inhibition of p53-mediated tumor suppressor genes. And, overexpression of MDM2 or AURKB reversed the promotive effects of PVT1 silence on the ADM sensitivity of ADM-resistant BC cell, and the inhibitory effect on expression multidrug resistance proteins. Mechanically, AURKB increased MDM2-mediated p53 ubiquitination. Taken together, PVT1 promoted BC cell proliferation and drug resistance via elevating MDM2 expression and AURKB-mediated p53 ubiquitination.

Evaluating the potency of blood long noncoding RNA PVT1 as candidate biomarker reflecting inflammation, multiple organ dysfunction, and mortality risk in sepsis patients.

ObjectiveLong noncoding RNA plasmacytoma variant translocation 1 (lnc‐PVT1) promotes septic inflammation and organ injuries via multiple ways, while its clinical engagement in sepsis management is indistinct. This study aimed to investigate its relationship with inflammation, multiple organ dysfunction, and mortality risk in sepsis patients.MethodsSepsis patients and age‐/gender‐matched healthy controls were enrolled; their lnc‐PVT1 expression in plasma were detected by RT‐qPCR. For sepsis patients only, the inflammatory cytokine levels (tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐17A) in plasma were detected by ELISA. According to the survival data during 28‐day follow‐up, sepsis patients were divided into sepsis survivors and sepsis deaths.ResultsLnc‐PVT1 expression was increased in sepsis patients (N = 157) compared with healthy controls (N = 80) (p < 0.001). In sepsis patients, lnc‐PVT1 was linked with higher acute physiology and chronic health evaluation II (APACHEII) score (p = 0.001), total sequential organ failure assessment (SOFA) score, and its most subitems (SOFA‐respiratory system, SOFA‐coagulation, SOFA‐liver, SOFA‐cardiovascular system, and SOFA‐renal system scores) (all p < 0.01), but not SOFA‐nervous system score (p = 0.091); it did not relate to primary infection sites either (p = 0.204). Furthermore, lnc‐PVT1 correlated with increased C‐reactive protein, TNF‐α, IL‐1β, and IL‐17 in sepsis patients (all p < 0.01). Additionally, lnc‐PVT1 expression was higher in sepsis deaths than that in sepsis survivors (p < 0.001), following receiver‐operating characteristic curve disclosed that lnc‐PVT1 predicted 28‐day septic mortality risk (area under the curve: 0.789, 95% confidence interval: 0.702–0.875).ConclusionCirculating lnc‐PVT1 exhibits the potential as a biomarker in sepsis patients to inform inflammation, multiple organ dysfunction, and mortality risk.

Up-regulated lncRNA-PVT1 expression in peripheral blood mononuclear cells of patients with coronary artery disease is correlated with decreased interleukin-10 production.

Plasmacytoma variant translocation 1 (PVT1) is a newly discovered long non-coding RNA, which has not been previously studied in the inflammatory responses of the peripheral blood mononuclear cells (PBMCs) of patients with coronary artery disease (CAD). This cross-sectional study was conducted on 15 CAD patients and 15 non-CAD (NCAD) individuals. The PVT1 expression was assessed in the PBMCs of the participants using a real-time polymerase chain reaction. Interleukin (IL)-10, IL-22, and matrix metalloproteinase-9 (MMP-9) were measured in the plasma and supernatant of cultured PBMCs in the presence or absence of lipopolysaccharide (LPS) using flow cytometry and enzyme-linked immunosorbent assay. An increased expression of PVT1 was observed in the untreated PBMCs of CAD patients, compared to the NCAD group. The PVT1 was significantly up-regulated after LPS treatment in the PBMCs of both groups. Plasma MMP-9 levels were found to be higher in CAD patients than in the control individuals. The level of IL-10 and IL-22 production by the non-treated PBMCs of CAD cases was significantly lower than the NCAD group. Overall, in the examined population, PVT1 expression was negatively correlated with IL-10 secretion. Moreover, the results showed a significant negative correlation between PVT1 expression and IL-10 production by untreated cells. The PVT1 expression augmented in the PBMCs of CAD patients, which could be associated with the decreased IL-10 generation by the PBMCs of these patients.

Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 gene (PVT1) modulates the proliferation and apoptosis of acute lymphoblastic leukemia cells by sponging miR-486-5p

ABSTRACT Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 gene (PVT1) is related to the progress of various cancers. Here, we illuminated the role of PVT1 in acute lymphoblastic leukemia (ALL) cell proliferation and apoptosis. PVT1 was upregulated in plasma samples from patients with ALL and ALL cell lines. PVT1 silencing repressed cell viability and enhanced cell apoptosis in Jurkat and SUP-B15 cells. PVT1 targeted microRNA-486-5p (miR-486-5p) and negatively modulated miR-486-5p expression. Upregulation of miR-486-5p decreased cell viability and increased ALL cell apoptosis. Mastermind Like Transcriptional Coactivator 3 (MAML3) was a downstream molecule of miR-486-5p and miR-486-5p mimic transfection weakened its expression in ALL cells. Rescue experiments proved that reintroduction of PVT1 counteracted the impacts of miR-486-5p in ALL cell proliferation and apoptosis. In vivo, PVT1 silencing repressed the tumor growth of SUP-B15 cells and reduced the expression of MAML3. Altogether, silencing of PVT1 inhibited ALL cell growth and induced cell apoptosis through sponging miR-486-5p.

Long non-coding RNA plasmacytoma variant translocation 1 correlates with higher inflammation, multiple organ injury and mortality risk in acute pancreatitis, especially in severe acute pancreatitis

Long non-coding RNA plasmacytoma variant translocation 1 (lnc-PVT1) possesses a good ability to regulate inflammation as well as multiple organ injury via multiple pathways, and clinically exacerbates severe acute pancreatitis (SAP) via autophagy. This study aimed to further assess the correlation of lnc-PVT1 with inflammation, multiple disease assessment scales, and prognostication in acute pancreatitis (AP) patients. Peripheral blood mononuclear cell (PBMC) samples were collected from 98 AP patients (within 24h after admission) and 50 healthy controls (HCs). lnc-PVT1 in PBMC samples was examined by reverse transcription-quantitive polymerase chain reaction. Multiple AP assessments, C-reactive protein (CRP) level, and in-hospital deaths were evaluated or recorded. lnc-PVT1 was overexpressed in AP patients compared with HCs; it was also positively correlated with Ranson's score, acute pathologic and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, and CRP level in AP patients. Besides, lnc-PVT1 disclosed a good predictive value for higher in-hospital mortality in AP patients (the area under the curve: 0.838, 95% confidence interval: 0.708-0.968). Lastly, lnc-PVT1 was generally correlated with CRP level as well as SOFA score among mild AP, moderate-severe AP, and SAP subgroups, especially in SAP subgroup; it was also correlated with higher mortality risk in SAP subgroup, but not in mild AP or moderate-severe AP subgroup. lnc-PVT1 is associated with CRP level, SOFA score, and higher mortality risk in AP patients, especially in SAP patients, indicating its potential as a biomarker for AP.

LncPVT1 regulates osteogenic differentiation of human periodontal ligament cells via miR-10a-5p/brain-derived neurotrophic factor.

Identifying the factors affecting osteoblast differentiation of periodontalligament cells(PDLCs) can help enhance the regeneration of periodontal tissue. LncRNA plasmacytoma variant translocation 1 (lncPVT1) is an important regulatory factor involved in many biological processes, but its role in osteogenesis remains unclear. Expressions of osteogenic markers were detected by quantitative reverse transcription polymerase chain reaction and Western blot analysis. Alkaline phosphatase staining was conducted for early osteoblast differentiation and alizarin red S staining was used for mineral deposition. RNA sequencing was used to identify the miRNAs regulated by lncPVT1 during osteogenesis. Cell transfection was used to overexpress or knockdown lncPVT1 and miR-10a-5p. Dual luciferase reporter assays were conducted to analyze the binding of miR-10a-5p to brain-derived neurotrophic factor (BDNF). LncPVT1 was significantly increased during osteogenic induction of PDLCs. Overexpression of lncPVT1 promoted osteogenesis, whereas lncPVT1 knockdown inhibited this process. RNA sequencing showed that miR-10a-5p expression was significantly increased after lncPVT1 knockdown. RNA immunoprecipitation assay further demonstrated the binding potential of lncPVT1 and miR-10a-5p. MiR-10a-5p inhibited the osteogenesis of PDLCs, and partially reversed the stimulatory effects of lncPVT1. Subsequently, we identified a predicted binding site for miR-10a-5p on BDNF and confirmed it using dual luciferase reporter assays. Moreover, lncPVT1 upregulated the expression of BDNF, whereas miR-10a-5p downregulated BDNF expression. BDNF promoted osteogenesis and partially rescued the si-lncPVT1-mediated inhibition of PDLCs osteogenic differentiation. LncPVT1 positively regulated the osteogenic differentiation of PDLCs via miR-10a-5p and BDNF. Our results provide a promising target for enhancing the osteogenic potential of PDLCs.

Knockdown of long non-coding RNA plasmacytoma variant translocation 1 relieves ox-LDL-induced endothelial cell injury through regulating microRNA-30c-5p in atherosclerosis

ABSTRACT Atherosclerosis (AS) is a chronic inflammatory disease involving endothelial dysfunction, and is one of the main causes of death from cardiovascular disease (CVD). Long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) is overexpressed in the serum of CVD patients. However, the mechanism by which lncRNA PVT1 functions in AS remains unknown. Our research was designed to probe interactions involving lncRNA PVT1 and oxidized low-density lipoprotein (ox-LDL)-stimulated endothelial cell injury in AS. lncRNA PVT1 expression in the serum of AS patients and ox-LDL-stimulated human umbilical vein endothelial cells (HUVECs) was detected using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Cell counting kit (CCK)-8 assays, flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA) were used to determine cell proliferation, apoptosis, and levels of inflammatory cytokines, respectively. Moreover, the correlation between lncRNA PVT1 and miR-30 c-5p was predicted and verified using StarBase3.0, TargetScan, and luciferase reporter-gene assays. lncRNA PVT1 was overexpressed in the serum of AS patients and in ox-LDL-stimulated HUVECs relative to controls. Knockdown of lncRNA PVT1 facilitated proliferation, reduced apoptosis, and secretion of inflammatory factors in ox-LDL-treated HUVECs. Moreover, miR-30 c-5p was verified as a direct target of lncRNA PVT1. Furthermore, we observed that miR-30 c-5p expression was lower in AS patients than in controls. In addition, the influence of lncRNA PVT1 knockdown on ox-LDL-treated HUVECs was significantly reversed by downregulation of miR-30 c-5p. In conclusion, lncRNA PVT1 silencing inhibited HUVEC damage stimulated by ox-LDL via miR-30 c-5p regulation.