Variant Translocation Research Articles

The lncRNA PVT1 promotes invasive growth of lung adenocarcinoma cells by targeting miR-378c to regulate SLC2A1 expression.

As an oncogene, plasmacytoma variant translocation 1 (PVT1) has been found to be highly expressed in several cancers. However, its specific role in lung adenocarcinoma (ADC) has not been fully elucidated. In this study, the expression of PVT1, miR-378c, and solute carrier family 2 member 1 (SLC2A1) was determined by quantitative real-time PCR and western blot. Dual-luciferase reporter assay was used to explore the relationship between PVT1 and miR-378c, as well as miR-378c and SLC2A1. The effects of PVT1 on the lung ADC cells proliferation, invasion, and migration were detected using MTT, wound-healing, and transwell assays. The results revealed that PVT1 was highly expressed in lung ADC cells, and the overexpression of PVT1 promoted the proliferation, migration, and invasion of lung ADC cells. In lung ADC cells, PVT1 negatively regulated miR-378c expression, and miR-378c negatively regulated SLC2A1 expression through binding to its 3'-untranslated coding regions. Knocking down of PVT1 inhibited the abilities of cell proliferation, migration, and invasion, while miR-378c inhibitor or SLC2A1 Vector diminished the effect. Together, silencing PVT1 downregulated SLC2A1 expression via targeting miR-378c, and then repressed lung ADC cells growth, migration, and invasion.

Long noncoding RNA plasmacytoma variant translocation gene 1 promotes epithelial-mesenchymal transition in osteosarcoma.

ObjectiveLong noncoding RNAs (lncRNAs) are involved in the proliferation, migration, and invasion of tumors. In the current study, our aim was to explore the role of lncRNA plasmacytoma variant translocation gene 1 (PVT1) in osteosarcoma.MethodsQuantitative real‐time reverse transcription‐polymerase chain reaction was used to detect the expression of lncRNA PVT1 in osteosarcoma tissues and cells. The relationship between lncRNA PVT1 expression status and the prognosis of patients with osteosarcoma was analyzed. The effect of lncRNA PVT1 on the malignant biological behavior of osteosarcoma cells in vitro was also analyzed.ResultsLncRNA PVT1 was upregulated in osteosarcoma. High lncRNA PVT1 expression indicated poor prognosis in patients with osteosarcoma. In vitro knockdown of lncRNA PVT1 inhibited the proliferation, migration, and invasion ability of osteosarcoma cells. In addition, we confirmed that lncRNA PVT1 affected the epithelial‐mesenchymal transition of osteosarcoma cells.ConclusionLncRNA PVT1 is a potential therapeutic target for osteosarcoma.

CLINICAL EFFICACY OF TARGETED THERAPY TOWARDS METASTATIC LUNG CANCER CARRYING DISTINCT TYPES OF ALK REARRANGEMENTS

Introduction . Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods . The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results . A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions . There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants.

Knockdown of PVT1 Suppresses Colorectal Cancer Progression by Regulating MiR-106b-5p/FJX1 Axis.

PurposeLong non-coding RNA plasmacytoma variant translocation 1 (PVT1) has been revealed to involve in the progression of CRC. However, the precise mechanisms of PVT1 in action remain unclear.MethodsThe expression of PVT1, microRNA-106b-5p (miR-106b-5p) and four jointed box 1 (FJX1) was measured using quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot, respectively. Cell proliferation was investigated by 3-(4,5)-dimethylthiahiazo (−z-y1)-3,5-di-phenytetrazoliumromide assay. Transwell assay was used to determine cell migration and invasion. The correlation between miR-106b-5p and PVT1 or FJX1 was confirmed using luciferase reporter assay. The effects of PVT1 in vivo were assessed using mice xenograft model.ResultsPVT1 was up-regulated in CRC tissues and cell lines, especially in CRC tissues with high-grade, and highly expressed PVT1 predicted worse prognosis. Functional experiments demonstrated that PVT1 deletion inhibited CRC cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. MiR-106b-5p was confirmed to be a target of PVT1, and inhibition of miR-106b-5p reversed the inhibitory effects of PVT1 knockdown on CRC cell malignant phenotypes. In addition, we found miR-106b-5p directly targeted FJX1, and miR-106b-5p-mediated inhibition on CRC cell proliferation, migration and invasion was attenuated by FJX1 up-regulation. Importantly, it was also proved that PVT1 could indirectly regulate FJX1 expression via targeting miR-106b-5p.ConclusionKnockdown of PVT1 impaired cell proliferation, migration and invasion in CRCs via regulating miR-106b-5p/FJX1 axis, which provided a novel insight into the development of therapeutic strategies for CRC patients.

LncRNA PVT1 Regulates TRPS1 Expression in Breast Cancer by Sponging miR-543.

BackgroundBreast cancer is the most common female malignancy with high invasion and metastasis abilities. Studies have shown that long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 gene (PVT1) is an oncogene and is positively correlated with progression and metastasis of breast tumors. However, the detailed mechanism of PVT1 in breast cancer tumorigenesis is not fully understood.MethodsReal-time polymerase quantitative chain reaction (RT-qPCR) was performed to identify the expression levels of PVT1, miR-543 and trichorhinophalangeal syndrome-1 gene (TRPS1) in breast cancer tissues and cells. Cell proliferation was measured by plate clone formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay. Apoptosis and motility of MCF-7 and MDA-MB-436 cells were assessed with flow cytometry assay and transwell migration and invasion analyses, respectively. In addition, a model was established to probe the function of PVT1 silencing in vivo. The target relationship among PVT1, miR-543 or TRPS1 was confirmed by dual-luciferase reporter analysis, RNA immunoprecipitation (RIP) and RNA pull down assays. The protein expression level of TRPS1 was evaluated with Western blot assay.ResultsPVT1 expression was upregulated in breast cancer tissues and cell lines. In addition, PVT1 silencing inhibited breast cancer cell growth and motility, while increased apoptosis. Meanwhile, the effects of PVT1 or miR-543 could be reversed by introducing overexpressed plasmid of miR-543 or TRPS1 in breast cancer cell lines, respectively.ConclusionKnockdown of PVT1 repressed breast cancer cell growth and motility, and induced apoptosis in vitro and reduced tumor volume and weight in vivo. Mechanically, the overexpression of PVT1 enhanced TRPS1 level by negatively targeted miR-543 in breast cancer.

PVT1 induces NSCLC cell migration and invasion by regulating IL-6 via sponging miR-760

Non-small-cell lung carcinoma (NSCLC) accounts for approximately 80% of lung cancers with a high metastatic potential. Elucidating the mechanism of NSCLC metastasis will provide new promising targets for NSCLC therapy and benefit its prognosis. Plasmacytoma variant translocation 1 (PVT1) has been proven to be overexpressed in NSCLC. Although the oncogenic role of PVT1 in NSCLC has been reported, its mechanism remains unclear. Here, we verified that the knockdown of PVT1 inhibited NSCLC cell migration and invasion, and that its inhibitory role on A549 cells and H1299 cells was antagonized by interleukin-6 (IL-6) treatment. The results revealed that PVT1 regulates IL-6 by sponging miR-760 and identified the binding site of miR-760 in the 3′-UTR of IL-6. In conclusion, a new mechanism was revealed, wherein PVT1 regulates NSCLC cell migration and invasion via miR-760/IL-6, suggesting PVT1/miR-760/IL-6 as promising prognostic biomarkers and therapeutic targets for NSCLC metastasis.

Abstract 639: Acute promyelocytic leukemia

Abstract Introduction: Acute Promyelocytic Leukemia (APL) accounts for 10%-15% of all acute myeloid leukemia's. The use of All-Trans Retinoic Acid/ Arsenic trioxide (ATRA/ATO) in the treatment regimens of low to intermediate-risk patients has led to remarkable cure rates (~80%). However, treatment guidelines of high-risk patients (WBC count≥ 10 x 109/L) remain unclear and these patients are at an increased risk of relapse. Design: Due to ambiguous treatment guidelines for high-risk APL patients as well as limited options for patients with arsenic resistant disease we sought to analyze clinical outcomes in this subset of patients. We conducted a literature search through Pubmed, EBSCO, and JSTOR to identify original articles that evaluated treatment protocols as well as outcomes for high-risk/refractory APL patients. We also evaluated the literature for clinical data involving patients who had arsenic resistant APL. Only relevant articles from 2000 to 2019 were included. Clinical trials where patients did not receive ATRA/ATO treatment were excluded. High risk patients have an increased mortality and decreased overall survival compared to intermediate and low risk patients. Although early death resulting from bleeding complications remains an important clinical hindrance, cases of arsenic resistant disease are becoming more prevalent. Resistant/refractory APL is a rare occurrence; however, no effective treatment exists to overcome resistance in this subset of patients. Of particular interest is the identification of variant translocations in APL; those that differ from the classical PML-RARA (~95%). 12 non-characteristic rearrangements have so far been described; of these, the ZBTB16-RARA and STAT5b-RARA are the most common variants. Both ZBTB16-RARA & STAT5b-RARA are insensitive to ATRA/ATO combination therapy, leaving these patients with limited options. Clinical outcomes have recently been described in a subset of 13 patients with arsenic resistant disease. Of these 13 patients with arsenic resistant disease, 11 eventually died. Mutations in a particular region of the PML protein have been shown to mediate arsenic resistant disease in both in vitro and in vivo models, suggesting a potential benefit of molecular screening to improve clinical outcomes. Neither ATO nor cytotoxic chemotherapy was successful in inducing remissions in this particular subset of patients. Conclusion: Well-defined treatment guidelines in high-risk APL and the need for alternative agents in patients resistant to ATO therapy are needed to improve clinical efficacy and outcomes. 1. Zhu, H.H.; Qin, Y.Z.; Huang, X.J. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 2014, 370, 1864-1866, doi:10.1056/NEJMc1316382. Citation Format: Ravinder Singh Chale, Joaquin J. Jimenez. Acute promyelocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 639.

Abstract 1411: Population level genetic differentiation at the PVT1 gene locus: Implications for prostate cancer

Abstract The incidence and mortality rate of prostate cancer (PCa) is highest in males of African ancestry. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. Analysis of data from the one thousand genomes project revealed that a 26-kb region spanning PVT1 exons 4A and 4B shows a run of 75 SNPs with distinct allelic frequencies between African and non-African populations. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa in males of African ancestry. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) present at 8q24 is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different functions. To investigate if our observed population-level differences at the PVT1 gene locus have implications for PCa, we determined the expression of PVT1 exons 4A and 4B in histologically confirmed normal prostate (n=22), benign tumor prostate (n=35), and malignant tumor prostate tissue (n=28) samples obtained from males who had undergone prostatectomy or transrectal ultrasound-guided biopsy in Nigeria, a sub-Saharan Black African population. We have observed that PVT1 exons 4A and 4B are significantly overexpressed in PCa tissues in comparison to others. Transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the possibility of exploiting them for diagnosis, therapy, and other clinical applications in PCa. Citation Format: Gargi Pal, Lia Di, Akintunde Orunmuyi, E. Oluwabunmi Olapade-Olaopa, Weigang Qiu, Olorunseun O. Ogunwobi. Population level genetic differentiation at the PVT1 gene locus: Implications for prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1411.

Tissue-based long non-coding RNAs “PVT1, TUG1 and MEG3” signature predicts Cisplatin resistance in ovarian Cancer

ObjectivesThe current study aimed to investigate the potentiality of three lncRNAs “Plasmacytoma variant translocation 1(lnc-PVT1), Taurine upregulated gene type 1(lnc-TUG1) and Maternally expressed gene 3 (lnc-MEG-3)”, to predict Cisplatin resistance in ovarian cancer (OC), in addition, to access their prognostic significance. MethodsThe expression level of lncRNAs were measured in 100 formalin-fixed paraffin-embedded tissue (FFET) samples of OC patients who were treated by Cisplatin-based chemotherapy using qPCR. ResultsThe results showed that lnc_PVT1 was significantly upregulated by 2.3 folds in Cisplatin resistant tissues, while, lnc-TUG1 and lnc-MEG3 were downregulated by 1.2 and 3 folds, respectively. In addition, the three lncRNAs exhibited high sensitivity and specificity in predicting chemo-resistance and they were negatively associated with OS and progression-free survival (p < 0.001). ConclusionThe lnc-PVT1, lnc-TUG1, and lnc-MEG3 transcriptome signatures could be used for predicting resistance to Cisplatin in OC patients.

Silencing of lncRNA PVT1 ameliorates streptozotocin-induced pancreatic β cell injury and enhances insulin secretory capacity by regulating miR-181a-5p.

Diabetes mellitus (DM) is a type of metabolic disorder characterized by long-term hyperglycemia. Accumulating evidence shows that long noncoding RNAs (lncRNAs) play significant roles in the occurrence and development of DM. This study intended to investigate the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in rat insulinoma (INS-1) cells damaged by streptozotocin (STZ) and to identify the potential mechanisms. Firstly, PVT1 expression in INS-1 cells was assessed using RT-qPCR after STZ stimulation. After PVT1-knockdown, cell apoptosis, the contents of oxidative stress related markers, and changes in insulin secretion were detected. Results indicated that PVT1 was remarkably upregulated after STZ stimulation. PVT1-knockdown inhibited STZ-induced oxidative stress and apoptosis of INS-1 cells. Moreover, the insulin secretory capacity was notably elevated following PVT1 silencing. Subsequently, a luciferase reporter assay verified that miR-181a-5p was directly targeted by PVT1. The rescue assays revealed that miR-181a-5p inhibitor dramatically abrogated the effects of PVT1 silencing on oxidative stress, apoptosis, and insulin secretion. Taken together, these findings demonstrated that PVT1-knockdown could ameliorate STZ-induced oxidative stress and apoptosis and elevate insulin secretory capacity in pancreatic β cells by regulating miR-181a-5p, suggesting a promising biomarker in DM diagnosis and treatment.

Circ-PVT1/miR-106a-5p/HK2 axis regulates cell growth, metastasis and glycolytic metabolism of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most commonly diagnosed oral cavity malignancy. A handful of circular RNAs (circRNAs) have recently shown to act as crucial regulators in OSCC, including circRNA plasmacytoma variant translocation 1 (circ-PVT1). However, further exploration is still needed for the underlying functional mechanism behind circ-PVT1 in OSCC. The levels of circ-PVT1, microRNA-106a-5p (miR-106a-5p) and hexokinase II (HK2) were all examined applying with quantitative real-time polymerase chain reaction (qRT-PCR). Cellular analyses (cell viability, apoptosis, metastasis and glycolysis) in vitro were performed via cell counting kit-8 (CCK-8), flow cytometry, transwell migration/invasion assays and glycolysis-related indications (glucose consumption, lactate production and ATP/ADP ratio). HK2 protein level was measured through western blot. Dual-luciferase reporter assay was conducted to study the interplay between miR-106a-5p and circ-PVT1 or HK2. Xenografts in mice were used for analyzing circ-PVT1 in vivo. Circ-PVT1 was expressed with abnormal high level while miR-106a-5p was down-regulated in OSCC tissues and cells. Circ-PVT1 knockdown reduced OSCC cell growth, metastasis and glycolysis. Moreover, circ-PVT1 acted in OSCC by functioning as a miR-106a-5p sponge. HK2 was a target of miR-106a-5p and miR-106a-5p played an anti-tumor role in OSCC by inhibiting HK2. Furthermore, HK2 could be regulated by circ-PVT1 via targeting miR-106a-5p. In xenograft models of mice, down-regulation of circ-PVT1 retarded tumorigenesis via the miR-106a-5p/HK2 axis. Our works suggested that circ-PVT1 directly combined with miR-106a-5p to mediate HK2 level, consequently regulating cellular behaviors in OSCC as a tumor promoter.

Effect of Long Non-Coding RNA Plasmacytoma Variant Translocation 1 (PVT1) on the Regulation of SRY (Sex Determining Region Y)-Box 2 (SOX2) in Gastric Cancer

The pathogenesis of gastric cancer (GC) is unclear, which has brought major problems in the diagnosis and treatment. LncRNAs is involved in the regulation of tumorigenesis and development. LncRNA PVT1 is abnormally expressed in various tumors, such as liver cancer and ovarian cancer. However, its role and mechanism in GC have not been clarified. The gastric cancer tissue and adjacent tissues were collected for measuring LncRNA PVT1 level by Real-time PCR. The gastric cancer cell line SGC-7901 was cultured in vitro and divided into control group, scramble group, and PVT1 siRNA group. The tetrazolium salt (MTT) colorimetric assay was to analyze cell proliferation. Caspase 3 activity was tested to assess cell apoptosis. Transwell chamber assay was adopted to evaluated cell invasion. Western Blot was for measuring the epithelial-mesenchymal transition (EMT) molecular proteins and SOX2. Significantly upregulated LncRNA PVT1 was found in gastric cancer tissue (P &lt; 0 05) which was associated tumor differentiation and stage and lymph node metastasis (P &lt; 0 05). LncRNA PVT1 siRNA transfection in SGC-7901 significantly downregulated LncRNA PVT1 expression, inhibited tumor cell proliferation, enhanced Caspase 3 activity, restrained gastric cancer cell invasion, elevated E-cadherin level, reduced Vimentin expression, and declined SOX2 expression (P &lt; 0 05). LncRNA PVT1 is upregulated in gastric cancer and related to the clinical pathology. Downregulation of LncRNA PVT1 inhibits cell proliferation, invasion, and EMT by regulating SOX2, thereby delaying the progression of gastric cancer.

LncRNA PVT1 Suppresses the Progression of Renal Fibrosis via Inactivation of TGF-β Signaling Pathway.

BackgroundRenal fibrosis is a frequent pathway leading to end-stage kidney dysfunction. In addition, renal fibrosis is the ultimate manifestation of chronic kidney diseases (CKD). Long noncoding RNAs (lncRNAs) are known to be involved in occurrence of renal fibrosis, and lncRNA plasmacytoma variant translocation 1 (PVT1) has been reported to act as a key biomarker in renal diseases. However, the role of PVT1 in renal fibrosis remains unclear.Materials and MethodsHK-2 cells were treated with TGF-β1 to mimic renal fibrosis in vitro. Gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of creatinine (CR) and blood urea nitrogen (BUN) in serum of mice. Additionally, unilateral ureteral obstruction (UUO)-induced renal fibrosis mice model was established to investigate the effect of PVT1 on renal fibrosis in vivo.ResultsPVT1 was upregulated in TGF-β1-treated HK-2 cells. In addition, TGF-β1-induced upregulation of α-SMA and fibronectin in HK-2 cells was significantly reversed by PVT1 knockdown. Meanwhile, PVT1 bound to miR-181a-5p in HK-2 cells. Moreover, miR-181a-5p directly targeted TGF-βR1. Furthermore, miR-181a-5p antagonist could significantly reverse the anti-fibrotic effect of PVT1 knockdown. Besides, knockdown of PVT1 notably attenuated the symptom of renal fibrosis in vivo.ConclusionKnockdown of PVT1 significantly inhibited the progression of renal fibrosis in vitro and in vivo. Thus, PVT1 may serve as a potential target for the treatment of renal fibrosis.

Long noncoding RNA PVT1 promotes tumor cell proliferation, invasion, migration and inhibits apoptosis in oral squamous cell carcinoma by regulating miR‑150‑5p/GLUT‑1.

Oral squamous cell carcinoma (OSCC) is a cancer with high morbidity and mortality. Research has demonstrated that long non-coding RNAs (lncRNAs) are critical for tumor initiation and development. In the present study, we aimed to ascertain the functions and potential mechanisms of lncRNA plasmacytoma variant translocation 1 (PVT1) in OSCC. Firstly, we found that the expression of PVT1 was increased in human OSCC tumor tissues and it was related to reduced survival of the patients. Furthermore, miR-150-5p expression was downregulated in OSCC tumor tissues and it was negatively related with PVT1. Moreover, GLUT-1 protein expression was upregulated in human OSCC tumor tissues. In addition, cell proliferation capacity was measured by CCK-8 assay and cell invasion and migration were measured by Transwell assay. PVT1 overexpression promoted cell proliferation, invasion and migration, while these effects were abrogated by PVT1 downregulation. In addition, luciferase gene reporter assay verified the miR-150-5p directly binds with PVT1, which regulates the biological functions of OSCC. Additionally, luciferase gene reporter assay confirmed that GLUT-1 was a target for miR-150-5p. The promotion of cell proliferation, invasion and migration in LV-PVT1-transfected cells was eliminated following miR-150-5p overexpression. Finally, in vivo nude mouse xenograft model further verified that PVT1 knockdown inhibited tumor growth, formation, invasion and migration. According to the results, PVT1 is increased in human OSCC tumor tissues, and is related to the poor prognosis of human OSCC patients. We uncovered a previously unappreciated PVT1/miR-150-5p/GLUT-1 signaling axis that promotes cell proliferation, invasion, migration and inhibits apoptosis in OSCC cell lines and in vivo, which suggests that this axis could be a target for the treatment of OSCC.

Biomarkers in Colorectal Cancer: Current Research and Future Prospects.

Colorectal cancer (CRC) is a leading cause of death worldwide, despite progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. Novel therapeutic agents have improved survival in both the adjuvant and advanced disease settings, albeit with an increased risk of toxicity and cost. However, metastatic disease continues to have a poor long-term prognosis and significant challenges remain due to late stage diagnosis and treatment failure. Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response. The past three decades have seen advances in genomics and molecular pathology of cancer biomarkers, allowing for greater individualization of therapy with a positive impact on survival outcomes. Clinically useful predictive biomarkers aid clinical decision making, such as the presence of KRAS gene mutations predicting benefit from epidermal growth factor receptor (EGFR) inhibiting antibodies. However, few biomarkers have been translated into clinical practice highlighting the need for further investigation. We review a range of protein, DNA and RNA-based biomarkers under investigation for diagnostic, predictive, and prognostic properties for CRC. In particular, long non-coding RNAs (lncRNA), have been investigated as biomarkers in a range of cancers including colorectal cancer. Specifically, we evaluate the potential role of lncRNA plasmacytoma variant translocation 1 (PVT1), an oncogene, as a diagnostic, prognostic, and therapeutic biomarker in colorectal cancer.

Upregulation of lncRNA plasmacytoma variant translocation 1 predicts poor prognosis in patients with muscle-invasive bladder cancer.

LncRNA plasmacytoma variant translocation 1 (PVT1) has been recognized as an oncogenic lncRNA, which participates in the migration and invasion of many kinds of cancer cells and the development of cancers. In the present study, we explored its clinical significance and prognostic value in muscle invasive bladder cancer (MIBC).A total of 98 MIBC patients’ samples were collected, who had undergone radical cystectomy from the March 2013 to December 2018. The associations between PVT1 expression and clinical data were calculated using the Chi2-test. Overall survival curves were determined by the Kaplan–Meier technique and contrasted via log-rank test. We utilized univariate and multivariate Cox proportional hazard models to examine the HR and 95% CI.The expression levels of PVT1 were significantly higher in MIBC tissues than that in normal bladder tissues (P < .001). PVT1 expression was significantly correlated with tumor grade (P = .009), margin (P = .002), T stage (P = .02), and lymph node metastasis (P < .001). MIBC patients with high PVT1 expression level had shorter overall survival than those with low PVT1 expression level (log-rank test, P = .004). Multivariate Cox regression analysis showed that PVT1 expression level (HR = 2.381, 95% CI: 1.821–7.012, P = .014) was an independent factor in predicting the overall survival of MIBC patients.In summary, increased PVT1 expression in MIBC patients is correlated with a higher MIBC stage and is significantly associated with poor prognosis for MIBC patients, which may provide new insights into new therapeutic strategy and postoperative intervention against bladder cancer.

Long Noncoding RNA PVT1 Promotes Prostate Cancer Metastasis by Increasing NOP2 Expression via Targeting Tumor Suppressor MicroRNAs.

BackgroundMetastatic disease caused by prostate cancer (PCa) is the principal cause of PCa-related mortality. Long non-protein-coding RNAs may possess significant cellular functions. Plasmacytoma variant translocation 1 (PVT1), a long non-coding RNA encoded by the human PVT1 gene, is an oncogene, which can regulate several tumor-related genes. In PCa, the function and mechanism of PVT1 are unclear. NOP2 is being pursued as a prognostic marker for cancer aggressiveness, which promotes mouse fibroblast growth and tumor formation. Essentially, nothing is known about the specific interactions between the PVT1 and NOP2.Methods 190 pairs of PCa tissues and adjacent normal tissues were collected and RNA sequencing was used to identify the differential lncRNAs. Real-time quantitative real-time PCR (RT-qPCR) confirmed these results and gene regulatory relationship. Lentiviral vectors were used to alter PVT1 and genes to analyze their effects on PCa progression. Transwell migration and invasion assays were performed to test the metastasis ability. Biofunction of PVT1 and NOP2 were confirmed in vitro and in vivo.ResultsIn this study, we reported that the long noncoding RNA-PVT1 was upregulated in PCa metastasis tissues and promoted migration of PCa cells in vitro and their metastasis in vivo. High levels of PVT1 significantly downregulated tumor suppressor microRNAs (miRNAs), such as miR-15b-5p, miR-27a-3p, miR-143-3p, and miR-627-5p, whose levels in metastasis tissues were low compared to those in non-metastasis tissues. In vitro and in vivo, PVT1 promotes PCa metastasis via targeting miRNAs. Furthermore, the expression level of PVT1 was positively associated with the expression of NOP2, a cancer metastasis-related protein. We demonstrated that NOP2 promoted invasion and migration of PCa. For specific mechanism, correlation analysis showed that PVT1 promoted metastasis by up-regulating NOP2.ConclusionTaken together, our results show that PVT1 acts as an inducer of PCa metastasis via targeting miRNAs, thereby promoting NOP2. This axis may have diagnostic and therapeutic potential for advanced PCa.

Population Differentiation at the PVT1 Gene Locus: Implications for Prostate Cancer.

Genetic variation in susceptibility to complex diseases, such as cancer, is well-established. Enrichment of disease associated alleles in specific populations could have implications for disease incidence and prevalence. Prostate cancer (PCa) is a disease with well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is present at chromosome 8q24 and is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different molecular and cellular functions. In an analysis of the PVT1 locus using data from the 1000 Genomes Project, we found the chromosomal region spanning PVT1 exons 4A and 4B to be highly differentiated between African and non-African populations. We further investigated levels of gene expression of PVT1 exons 4A and 4B and observed significant overexpression of these exons in PCa tissues relative to benign prostatic hyperplasia and to normal prostate tissues obtained from men of African ancestry. These results indicate that PVT1 exons 4A and 4B may have clinical implications in PCa a conclusion supported by the observation that transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the development of diagnostic, therapeutic, and other clinical applications in PCa.

Lowly expressed lncRNA PVT1 suppresses proliferation and advances apoptosis of glioma cells through up-regulating microRNA-128-1-5p and inhibiting PTBP1

BackgroundGlioma is a primary intracranial malignancy with poor prognosis, of which the pathogenesis remains to be elucidated. Therein, the aim of this study is to discuss the impacts of lncRNA plasmacytoma variant translocation 1 (PVT1)/microRNA-128−1-5p (miR-128−1-5p)/polypyrimidine tract-binding protein 1 (PTBP1) axis on the biological characteristics of glioma cells. MethodsGlioma tissue samples (72 cases) and normal brain tissue samples (35 cases) were harvested. The expression of PVT1, miR-128−1-5p and PTBP1 in glioma tissues and cells was detected. Glioma cells were transfected with sh-PVT1, miR-128−1-5p mimics or miR-128−1-5p inhibitors to verify the impacts of PVT1 and miR-128−1-5p on DNA damage, cell colony formation, invasion, proliferation, migration and apoptosis of glioma U87 and U251 cells. The growth of transplanted tumor was tested by tumor xenograft in nude mice. The combination of PVT1 and miR-128−1-5p and the targeting relationship between miR-128−1-5p and PTBP1 were verified. ResultsPVT1 and PTBP1 expression was enhanced and miR-128−1-5p expression was degraded in glioma tissues and cells. Overexpressed miR-128−1-5p and lowly-expressed PVT1 promoted DNA damage, suppressed colony formation, invasion, proliferation and migration as well as boosted apoptosis of U251 and U87 cells. Up-regulating miR-128−1-5p and down-regulating PVT1 reduced transplanted tumor volume and weight of glioma in mice. Low expression miR-128−1-5p reversed the effect of low expression PVT1 on the biological characteristics of glioma cells. PVT1 specifically bound to miR-128−1-5p and PTBP1 was the target gene of miR-128−1-5p. ConclusionThis study suggests that down-regulated PVT1 or up-regulated miR-128−1-5p boosts apoptosis and attenuates proliferation of glioma cells by inhibiting PTBP1 expression. This study is essential for finding new therapeutic targets for glioma.

Long non-coding RNA PVT1-mediated miR-543/SERPINI1 axis plays a key role in the regulatory mechanism of ovarian cancer.

Purpose: To investigate the regulation mechanism of long non-coding RNA (lncRNA) plasmocytoma variant translocation 1 (PVT1) in ovarian cancer (OC).Methods: The levels of PVT1, microRNA (miR)-543, serpin peptidase inhibitor-clade I (neuroserpin)-member 1 (SERPINI1) in OC tissues and OVCAR-3, A2780, TOV-112D of OC cell lines were detected by quantitative real-time PCR (qRT-PCR) and Western Blot (WB). Cell proliferation, migration, invasion, apoptosis and the regulatory relationship between genes and target genes were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell, flow cytometry and dual luciferase reporter (DLR). The OC patients were followed up for 5 years to analyze the relationship between PVT1 and 5-year overall survival (OS).Results: In contrast with miR-543, PVT1 and SERPINI1 were highly expressed in OC tissues and cell lines, and high levels of PVT1 were significantly associated with lower 5-year OS of patients. Down-regulating PVT1 not only inhibited the malignant proliferation, migration and invasion of OC cells, but promoted cell apoptosis. PVT1 regulated miR-543 in a targeted manner, and its overexpression could attenuate the anticancer effect of miR-543 on OC cells. In addition, miR-543 also directly targeted SERPINI1, and miR-543 knockdown weakened the inhibitory effect of down-regulated SERPINI1 on OC progression. Furthermore, we found that PVT1 acted as a competitive endogenous RNA to sponge miR-543, thereby regulating the expression of SERPINI1.Conclusion: PVT1 can mediate the molecular mechanism of OC by miR-543/SERPINI1 axis regulatory network, which is a new therapeutic direction for OC.