Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

Angiogenesis can aggravate gastric cancer progression. LncRNAs exert important roles in regulating various cancer behaviors. However, the functions and mechanisms of lncRNAs in angiogenesis remain largely unknown. Here we demonstrated that lncRNA PVT1 was upregulated and significantly associated with high-microvessel density and poor prognosis in gastric cancer. Through gain- and loss-of PVT1 expression, we found PVT1 could obviously induce angiogenesis within tumors, in addition to promoting tumor growth in vitro and in vivo. Mechanistically, PVT1 directly interacted with the signal transducer activator phospho-STAT3 in the nucleus, and increased its protein stability by protecting it from poly-ubiquitination and proteasome-dependent degradation. The binding of PVT1 activated the STAT3 signalling pathway, and successively elevated VEGFA expression to stimulate angiogenesis. The positive correlation of PVT1 and VEGFA expression was also verified in gastric cancer specimens, and high levels of PVT1 and VEGFA in combination frequently predicted shorter survival time. Moreover, we revealed that PVT1 was a STAT3-responsive lncRNA, as STAT3 could occupy the PVT1 promoter to facilitate its transcription. The positive feed-back loop of PVT1 and STAT3 continuously enhanced the oncogenic effects. Collectively, our study first elucidates the mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis, which provides promising target for developing new therapeutic strategy in gastric cancer.

LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer.

The extracellular matrix (ECM) constitutes a highly dynamic three-dimensional structural network comprised of macromolecules, such as proteoglycans/glycosaminoglycans (PGs/GAGs), collagens, laminins, fibronectin, elastin, other glycoproteins and proteinases In recent years, the field of PGs has expanded rapidly Due to their high structural complexity and heterogeneity, PGs mediate several homeostatic and pathological processes PGs consist of a protein core and one or more covalently attached GAG chains, which provide the protein cores with the ability to interact with several proteins The GAG building blocks of PGs significantly influence the chemical and functional properties of PGs The primary goal of this comprehensive review is to summarize major achievements and paradigm-shifting discoveries made on the PG/GAG chemistry-biology axis, focusing on structural variability, structure-function relationships, metabolic, molecular, and epigenetic mechanisms underlying their synthesis Recent insights related to exosome biogenesis, degradation, and cell signaling, their status as diagnostic tools and potential pharmacological targets in diseases as well as current applications in nanotechnology and biotechnology are addressed Moreover, issues related to docking studies, molecular modeling, GAG/PG interaction networks, and their integration are discussed

Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics.

FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010 However, the mechanism of FOXM1 dysregulation remains indistinct A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1

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Regulation of the master regulator FOXM1 in cancer

The long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been reported to be overexpressed in colorectal cancer (CRC) However, its underlying mechanisms in the progression of CRC have not been well studied To investigate the clinical significance of NEAT1, we analyzed its expression levels in a publicly available dataset and in 71 CRC samples from Fudan University Shanghai Cancer Center Functional assays, including the CCK8, EdU, colony formation, wound healing, and Transwell assays, were used to determine the oncogenic role of NEAT1 in human CRC progression Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and Dual-Luciferase Reporter Assays were used to determine the mechanism of NEAT1 in CRC progression Animal experiments were used to determine the role of NEAT1 in CRC tumorigenicity and metastasis in vivo NEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues Altered NEAT1 expression led to marked changes in proliferation, migration, and invasion of CRC cells both in vitro and in vivo Mechanistically, we found that NEAT1 directly bound to the DDX5 protein, regulated its stability, and sequentially activated Wnt signaling Our study showed that NEAT1 indirectly activated the Wnt/β-catenin signaling pathway via DDX5 and fulfilled its oncogenic functions in a DDX5-mediated manner Clinically, concomitant NEAT1 and DDX5 protein levels negatively correlated with the overall survival and disease-free survival of CRC patients Our findings indicated that NEAT1 activated Wnt signaling to promote colorectal cancer progression and metastasis The NEAT1/DDX5/Wnt/β-catenin axis could be a potential therapeutic target of pharmacological strategies

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The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5.

Purpose: The long, noncoding RNA (lncRNA) PVT1 is an important epigenetic regulator with a critical role in human tumors. Here, we aimed to investigate the clinical application and the potential molecular mechanisms of PVT1 in gastric cancer tumorigenesis and progression.Experimental Design: The expression level of PVT1 was determined by RT-qPCR analysis in 190 pairs of gastric cancer tissues and adjacent normal gastric mucosa tissues (ANT). The biologic functions of PVT1 were assessed by in vitro and in vivo functional experiments. RNA protein pull-down assays and LS/MS mass spectrometry analysis were performed to detect and identify the PVT1- interacting protein FOXM1. Protein-RNA immunoprecipitation assays were conducted to examine the interaction of FOXM1 and PVT1 Chromatin immunoprecipitation (ChIP) and luciferase analyses were utilized to identify the binding site of FOXM1 on the PVT1 promoter.Results: The lncRNA PVT1 was significantly upregulated in gastric cancer tissues compared with ANTs. High expression of PVT1 predicted poor prognosis in patients with gastric cancer. PVT1 enhanced gastric cancer cell proliferation and invasion in vitro and in vivoPVT1 directly bound FOXM1 protein and increased FOXM1 posttranslationally. Moreover, PVT1 is also a FOXM1-responsive lncRNA, and FOXM1 directly binds to the PVT1 promoter to activate its transcription. Finally, PVT1 fulfilled its oncogenic functions in a FOXM1-mediated manner.Conclusions: Our study suggests that PVT1 promotes tumor progression by interacting with FOXM1. PVT1 may be a valuable prognostic predictor for gastric cancer, and the positive feedback loop of PVT1-FOXM1 could be a therapeutic target in pharmacologic strategies. Clin Cancer Res; 23(8); 2071-80. ©2016 AACR.

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A Positive Feedback Loop of lncRNA-PVT1 and FOXM1 Facilitates Gastric Cancer Growth and Invasion.

Pseudogenes play a crucial role in cancer progression. However, the role of pituitary tumour-transforming 3, pseudogene (PTTG3P) in gastric cancer (GC) remains unknown. Here, we showed that PTTG3P expression was abnormally up-regulated in GC tissues compared with that in normal tissues both in our 198 cases of clinical samples and the cohort from The Cancer Genome Atlas (TCGA) database. High PTTG3P expression was correlated with increased tumour size and enhanced tumour invasiveness and served as an independent negative prognostic predictor. Moreover, up-regulation of PTTG3P in GC cells stimulated cell proliferation, migration and invasion both in vitro in cell experiments and in vivo in nude mouse models, and the pseudogene functioned independently of its parent genes. Overall, these results reveal that PTTG3P is a novel prognostic biomarker with independent oncogenic functions in GC.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.13239

PTTG3P promotes gastric tumour cell proliferation and invasion and is an indicator of poor prognosis

Gastric cancer (GC) is the leading malignancy in the digestive system. Versican is a ubiquitous component of the extracellular matrix and has a role in tumor progression. We aim to examine the expression of Versican in GC and the relationship between Versican levels and patient survival. We detected the mRNA expression of Versican in tumorous pairs and adjacent normal tissues (ANTs) of 78 GC patients by quantitative real-time polymerase chain reaction. The protein expression of Versican in 101 cases of matched GC and ANT, as well as in 27 intraepithelial neoplastic (IN) samples, was evaluated by immunohistochemistry. We analyzed the correlation between Versican levels and clinical outcomes. Finally, we performed CCK-8 cell counting assay and transwell assay in GC cell lines. Versican mRNA expression was significantly greater in tumor tissues (P<0.001) than in ANT. Versican was majorly expressed in the stroma surrounding tumor epithelium and minorly some areas of tumor epithelium. The Versican expression level was higher in GC than in ANT (P=0.004), but no significant difference was observed between ANT and IN (P=0.517). The Versican mRNA and protein levels were consistent in GC. High Versican mRNA and protein expression correlated with greater tumor invasion depth (P=0.030, P=0.027). Univariate and multivariate analysis revealed that patients with high Versican mRNA expression exhibited poor disease-specific survival (P<0.001). In vitro experiments showed that Versican overexpression promoted cell proliferation and invasion. Our data indicate that Versican may be a novel prognostic indicator in GC and may be a potential target for clinical diagnosis.

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Wei Zhang

Papers

A Positive Feedback Loop of lncRNA-PVT1 and FOXM1 Facilitates Gastric Cancer Growth and Invasion.

PTTG3P promotes gastric tumour cell proliferation and invasion and is an indicator of poor prognosis

Prognostic significance of Versican expression in gastric adenocarcinoma