Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

INTRODUCTION: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.

Engineering M2-type macrophages with a metal polyphenol network for peripheral artery disease treatment.

Functional cell treatment for critical limb ischemia is limited by cell viability loss and dysfunction resulting from a harmful ischemic microenvironment. Metal-polyphenol networks have emerged as novel cell delivery vehicles for protecting cells from the detrimental ischemic microenvironment and prolonging the survival rate of cells in the ischemic microenvironment. M2 macrophages are closely related to tissue repair, and they secrete anti-inflammatory factors that contribute to lesion repair. However, these cells are easily metabolized in the body with low efficiency. Herein, M2 macrophages were decorated with a metal‒polyphenol network that contains copper ions and epigallocatechin gallate (Cu-EGCG@M2) to increase cell survival and therapeutic potential. Cu-EGCG@M2 synergistically promoted angiogenesis through the inherent angiogenesis effect of M2 macrophages and copper ions. We found that Cu-EGCG@M2 increased in vitro viability and strengthened the in vivo therapeutic effect on the ischemic hindlimbs of mice, which promoted the recovery of blood and muscle regeneration, resulting in superior limb salvage. These therapeutic effects were ascribed to the increased survival rate and therapeutic period of M2 macrophages, as well as the ameliorated microenvironment at the ischemic site. Additionally, Cu-EGCG exhibited antioxidant, anti-inflammatory, and proangiogenic effects. Our findings provide a feasible option for cell-based treatment of CLI.

Metal-phenolic capsules with ROS scavenging reshape the oxidative microenvironment of atherosclerosis.

Arterial injury makes the tissue in a state of high oxidative stress. At the same time, abnormal lipid metabolism can further lead to bleeding and thrombosis. Therefore, the anti-inflammatory and anti-oxidant polyphenol, EGCG was organically complexed with Fe3+ to form a metal-phenolic framework carrier. And the antihyperlipidemic drug, atorvastatin (ATV) was loaded into the carrier to enhance the bioavailability, and simultaneously alleviate the oxidative stress of the inflammatory site and abnormal lipid metabolism. The results confirmed that the obtained material EGCG-Fe-ATV had good biocompatibility and biosafety effect. In addition, EGCG-Fe-ATV showed outstanding anti-inflammatory, anti-oxidant and lipid-lowering properties. These therapeutic outcomes of EGCG-Fe-ATV were achieved by reducing systemic and local oxidative stress and inflammation, alleviating inflammatory cell infiltration in plaques, and modulating lipid synthesis and transferase to alter cholesterol transport. In conclusion, the combination of metal-phenolic capsules with ATV provides a new strategy for reshaping the oxidative microenvironment of atherosclerosis.

Synergy of antioxidant and M2 polarization in polyphenol-modified konjac glucomannan dressing for remodeling wound healing microenvironment.

Effective skin wound healing and tissue regeneration remain a challenge. Excessive/chronic inflammation inhibits wound healing, leading to scar formation. Herein, we report a wound dressing composed of KGM-GA based on the natural substances konjac glucomannan (KGM) and gallic acid (GA) that accelerates wound healing without any additional drugs. An in vitro study showed that KGM-GA could not only stimulate macrophage polarization to the anti-inflammatory M2 phenotype but also decrease reactive oxygen species (ROS) levels, indicating excellent anti-inflammatory properties. Moreover, in vivo studies of skin wounds demonstrated that the KGM-GA dressing significantly improved wound healing by accelerating wound closure, collagen deposition, and angiogenesis. In addition, it was observed that KGM-GA regulated M2 polarization, reducing the production of intracellular ROS in the wound microenvironment, which was consistent with the in vitro experiments. Therefore, this study designed a multifunctional biomaterial with biological activity, providing a novel dressing for wound healing.

Redox Modulatory Cu(II)-Baicalein Microflowers Prepared in One Step Effectively Promote Therapeutic Angiogenesis in Diabetic Mice.

Reactive oxygen species (ROS) have been implicated in multiple cellular processes, and an imbalance in redox homeostasis gives rise to diseases, therefore, reestablishing redox homeostasis is a way to cure. Here, copper-based metal-organic networks (Cu-MON) are generated by one-step reaction using anti-inflammatory and antioxidant baicalein as organic ligand and pro-angiogenic copper as metal ions. Phosphate buffered saline is required for triggering Cu-MON formation, and baicalein regulates the morphology and particle size of Cu-MON. Cu-MON are composed of Cu-baicalein complexes (82.08 wt%) and Cu3 (PO4 )2 ·3H2 O (17.92 wt%), thus exhibit a variable catalase-like activity against different H2 O2 levels due to the reversible change between Cu2+ /Cu1+ /Cu0 species. Intramuscular injection of Cu-MON significantly increases blood flow of ischemic limb in diabetic mice, enhances the relative activities of redox-related enzymes in ischemic muscle, thus effectively ameliorating the oxidative damage. Taken together, through moderate and dynamic "precise homeostasis regulation of cells," Cu-MON can be an efficient therapeutic strategy for peripheral arterial disease with diabetic complications.

RNA m6A regulates transcription via DNA demethylation and chromatin accessibility.

Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N6-methyladenosine (m6A) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA m6A, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA m6A formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA m6A and DNA modification in physiologic and pathogenic process.

In situ release of IL-2/IL-12 from SiO2-engineered dendritic cells for synergistic immunotherapy.

Herein, a synergistic therapy strategy of cytokine and dendritic cell (DC) vaccine was developed via the chemical conjugation of cytokine-loaded SiO2 directly on the plasma membrane of DCs. Firstly, IL-2/IL-12-loaded SiO2 was prepared and modified with MAL-PEG-NHS, and then coupled on the membrane of mature DCs through the coupling of -MAL and -SH groups. The large surface area and bimodal pores of SiO2 endowed it with high cytokine loading capacity and entrapment efficiency (EE%), with EEIL-2% of 95.8% and EEIL-12% of 86.4%. SiO2 was stably attached to the surface of DCs, and thus not internalized by mature DCs, and the SiO2 conjugation blocked only 4.37% of the total available cell surface thiol groups. After SiO2 attachment, the cell viability, membrane integrity and intracellular reactive oxygen species (ROS) of DCs were not affected. Furthermore, this strategy avoids the systemic toxicity of cytokines and improves the ability of DCs to target lymph nodes. IL-2 and IL-12 were only released locally around DCs, enabling the pseudo-autocrine stimulation of the transferred DCs in vivo. Moreover, the long-term anti-tumor protection in a B16 tumor model was demonstrated. This strategy is a facile and generalizable dendritic cell-based cancer immunotherapy strategy to augment bioavailability, while minimizing the side effects of cytokines.

Corrigendum to "ROS-responsive nanoparticle-mediated delivery of CYP2J2 gene for therapeutic angiogenesis in severe hindlimb ischemia" [Materials Today Bio 13(2022) 100192].

[This corrects the article DOI: 10.1016/j.mtbio.2021.100192.].

Absorption enhancement in visible range from Fano resonant silicon nanoparticle arrays embedded in single crystal Mg:Er:LiNbO3synthesized by direct ion implantation.

Fano resonant Si nanoparticles (NPs) are synthesized in single-crystal Mg:Er:LiNbO3using ion implantation and subsequent thermal annealing. The structural and optical properties of the Si NPs embedded in the crystal have been investigated. Spherical particles with radius of about 60 nm are observed by cross-sectional transmission electron microscope, while ion beam analysis are used to characterize the NPs formation process. The absorption of the Mg:Er:LiNbO3crystals have been enhanced significantly due to the embedded Si NPs, which are induced by the Fano resonance effect in the visible light wavelength band. Periodic structures of spherical Si particles model is proposed and analyzed using the Mie theory to study the optical response features and local fields. As a result, numerical simulations demonstrate that periodicities of the array of Si NPs can yield narrow resonant peaks connected with multiple light scattering by the NPs and displaying a Fano-type resonant profile. The wavelengths of the absorption peak show clear red shift with increasing the radius of NPs and the peak intensity can be enhanced by decreasing the array period. This work opens an avenue to modulate the optical filed by embedding Fano resonant Si NPs for potential application in optical devices.

H2O2-responsive VEGF/NGF gene co-delivery nano-system achieves stable vascularization in ischemic hindlimbs.

Peripheral vascular disease (PVD) is a common clinical manifestation of atherosclerosis. Vascular endothelial growth factor (VEGF) gene therapy is a promising approach for PVD treatment. However, due to single-gene therapy limitations and high H2O2 pathological microenvironment, VEGF gene therapy are not as expectations and its clinical application are limited. Synergistic effects of Nerve factors and vascular factors in angiogenesis have attracted attention in recent years. In this study, VEGF and nerve growth factor (NGF) genes co-delivery nanoparticles (VEGF/NGF-NPs) were prepared by using H2O2 responsive 6s-PLGA-Po-PEG as a carrier. 6s-PLGA-Po-PEG could react with H2O2 specifically due to the internal peroxalate bond. Angiogenic effects of VEGF/NGF-NPs has been evaluated in cells and hindlimb ischemia mice model. Results showed that VEGF/NGF-NPs promoted VEGF and NGF co-expression simultaneously, eliminated excessive H2O2, strengthened reactions between SH-SY5Ys and HUVECs, and finally enhanced migration, tube formation, proliferation and H2O2 damage resistance of HUVECs. VEGF/NGF-NPs also recovered blood perfusion, promoted the expression of VEGF, NGF, eNOS and NO, and enhanced vascular coverage of pericytes. Treatment effects of VEGF/NGF-NPs may related to VEGF/eNOS/NO pathway. Altogether, VEGF/NGF-NPs eliminated excessive H2O2 while achieving gene co-delivery, and promoted stable angiogenesis. It's a promising way for PVD treatment by using VEGF/NGF-NPs.

ROS-responsive nanoparticle-mediated delivery of CYP2J2 gene for therapeutic angiogenesis in severe hindlimb ischemia.

With critical limb ischemia (CLI) being a multi-factorial disease, it is becoming evident that gene therapy with a multiple bio-functional growth factor could achieve better therapeutic outcomes. Cytochrome P450 epoxygenase-2J2 (CYP2J2) and its catalytic products epoxyeicosatrienoic acids (EETs) exhibit pleiotropic biological activities, including pro-angiogenic, anti-inflammatory and cardiovascular protective effects, which are considerably beneficial for reversing ischemia and restoring local blood flow in CLI. Here, we designed a nanoparticle-based pcDNA3.1-CYP2J2 plasmid DNA (pDNA) delivery system (nanoparticle/pDNA complex) composed of a novel three-arm star block copolymer (3S-PLGA-po-PEG), which was achieved by conjugating three-armed PLGA to PEG via the peroxalate ester bond. Considering the multiple bio-functions of CYP2J2-EETs and the sensitivity of the peroxalate ester bond to H2O2, this nanoparticle-based gene delivery system is expected to exhibit excellent pro-angiogenic effects while improving the high oxidative stress and inflammatory micro-environment in ischemic hindlimb. Our study reports the first application of CYP2J2 in the field of therapeutic angiogenesis for CLI treatment and our findings demonstrated good biocompatibility, stability and sustained release properties of the CYP2J2 nano-delivery system. In addition, this nanoparticle-based gene delivery system showed high transfection efficiency and efficient VEGF expression in vitro and in vivo. Intramuscular injection of nanoparticle/pDNA complexes into mice with hindlimb ischemia resulted in significant rapid blood flow recovery and improved muscle repair compared to mice treated with naked pDNA. In summary, 3S-PLGA-po-PEG/CYP2J2-pDNA complexes have tremendous potential and provide a practical strategy for the treatment of limb ischemia. Moreover, 3S-PLGA-po-PEG nanoparticles might be useful as a potential non-viral carrier for other gene delivery applications.

Investigation of optical absorption enhancement of plasmonic configuration by graphene on LiNbO3-SiO2structure.

A novel plasmonic structure is demonstrated by combining graphene with a planar LiNbO3thin layer, which is simple and easy to fabricate compared to the complex design of general graphene surface plasmons devices. Graphene from the chemical vapor deposition is investigated and characterized to be a continuous and uniform monolayer or fewlayer. LiNbO3capped by graphene layer show an extraordinary absorption enhancement in an attenuated total reflection (ATR) measurement at a wide bandwidth of 500-4000 cm-1, which can be explained by resonance absorption resulting from the coupling of graphene surface plasmons with optical modes of LiNbO3-SiO2Fabry-Perot cavity and LiNbO3planar waveguide. The simulation results are generally consistent with the ATR experimental results. The absorption spectra versus temperature of this plasmonic configuration is also investigated, which show that increasing the testing temperature not only highlights the atomic vibrational peaks of graphene, but also enhances the absorption at several characteristic absorption frequencies due to the enhanced coupling between the surface plamons excitations and the optical modes.

N6 -methyladenosine-Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression.

Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene WTAPP1 in the progress of pancreatic ductal adenocarcinoma (PDAC). WTAPP1 RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of WTAPP1 RNA promoted PDAC proliferation and invasiveness in vitro and in vivo. Mechanistically, N 6-methyladenosine (m6A) modification stabilized WTAPP1 RNA via CCHC-type zinc finger nucleic-acid binding protein (CNBP), resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WT1-associated protein (WTAP) mRNA and recruited more EIF3 translation initiation complex to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m6A-mediated increases in WTAPP1 expression promote PDAC progression and thus may serve as a therapeutic target. SIGNIFICANCE: This study reveals how aberrant m6A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.

Investigation of novel optical and waveguide characteristics for an air-graphene-LiNbO3system.

The optical characteristics of a planar thin film waveguide system composed of air-graphene-LiNbO3have been investigated. Monolayer or bilayer graphene of high quality are characterized by Raman spectroscopy, scanning electron microscopy and atomic force microscopy. The refractivity and reflectivity of the air-graphene-LiNbO3system are measured experimentally and compared with those of a LiNbO3waveguide by the prism coupling method. The reflectivity shows an overall decrease due to the lower transmittance for graphene on the LiNbO3substrate. The refractivity increases significantly at the wavelength of 1540 nm, which may be attributed to the generation of graphene surface plasmons excited by infrared radiation. A shaped air-graphene-LiNbO3waveguide is designed and simulated by Mode Solutions. The distribution of an optical field is performed and analyzed. The preparation of the proposed air-graphene-LiNbO3structure incorporates the commonly used chemical vapor deposition and thin film transfer techniques, and is compatible with existing optoelectronic integration processes, which can be employed for building various optical integrated devices.

Enhancement of near-infrared photoluminescence in Mg:Er:LiNbO3 containing Au nanoparticles synthesized by direct ion implantation.

Embedded gold (Au) nanoparticles (NPs) are formed in Mg:Er:LiNbO3 single crystals by Au ion implantation and subsequent thermal annealing. Absorption of the Mg:Er:LiNbO3 crystals with Au NPs is found to be enhanced significantly in the visible light wavelength band owing to the localized surface plasmon resonance (LSPR) effect. The calculated LSPR effect by Mie theory shows good agreement with the absorption spectra. A significantly enhanced Er related photoluminescence (PL) at 1.54 µm for crystals with Au NPs is also observed compared with samples without Au NPs. Energy transfer between Au NPs and Er is found to be responsible for the PL enhancement in the as-implanted samples while local field enhancement induced by LSPR is considered the dominant factor in the annealed samples. The dependence of PL enhancement on NP size makes it possible to tailor intensity by varying the annealing temperature. An avenue to enhance and modulate the PL of dielectrics with embedding Au NPs synthesized by ion implantation is presented in this study.

A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control.

BACKGROUND & AIMS: Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes. METHODS: Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (IkkßΔHep) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/ß signaling-(IfnarΔHep), or interferon-α/ß signaling in myeloid cells-(IfnarΔMyel) were infected. RESULTS: Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected IkkßΔHep livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8+ T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKß, demonstrating a hepatocyte-intrinsic effect. Similar to livers of IkkßΔHep mice, enhanced hepatocytic LCMV accumulation was observed in livers of IfnarΔHep mice, whereas IfnarΔMyel mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/ß-mediated inhibition of HBV replication in vitro. CONCLUSIONS: Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/ß signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance. LAY SUMMARY: Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication.

A choline chloride-acrylic acid deep eutectic solvent polymer based on Fe3O4 particles and MoS2 sheets (poly(ChCl-AA DES)@Fe3O4@MoS2) with specific recognition and good antibacterial properties for ß-lactoglobulin in milk.

With the development of deep eutectic solvents (DESs), more DES-based functional materials have been explored and applied in various areas. In this work, a novel choline chloride-acrylic acid (ChCl-AA) DES polymer, on a 2D magnetic base, was prepared for the recognition of ß-lactoglobulin (ß-LG) biomacromolecules in milk and for the inhibition of common bacteria such as Escherichia coli (E. coli), Pseudomonas fluorescens (P. fluorescens), Staphylococcus aureus (S. aureus), and Bacillus subtilis (B. subtilis). The ChCl-AA DESs were polymerized on the surface of 2D MoS2 sheets doped with nano Fe3O4 particles, and the resulting polymer was abbreviated poly(ChCl-AA DES)@Fe3O4@MoS2. The free energy (ΔG=-92) of ChCl-AA DES was calculated using the Gaussian software, the composition and structure of poly(ChCl-AA DES)@Fe3O4@MoS2 were characterized by field emission scanning electron microscopy, transmission electron microscopy, etc., the qualitative and quantitative analyses of ß-LG were done by fluorescence spectra, sodium dodecyl sulfate polyacrylamide gel electrophoresis and high performance liquid chromatography, and the bioactivity of bacteria was analyzed by flat colony counting. Based on the present analysis, poly(ChCl-AA DES)@Fe3O4@MoS2 specifically recognized ß-LG in a good fitting Langmuir isotherm (R2 = 0.9909) and second-order kinetic model (R2 = 0.9989) by affinity, and evidently inhibited three bacteria, namely, E. coil (65%), S. aureus (50%), and B. subtilis (54%), effectively reducing the relative colony number. As the poly(ChCl-AA DES)@Fe3O4@MoS2 material did not only exhibit specific recognition of biomacromolecules, but also had an antimicrobial effect against common bacteria, it could be an ideal separation media or carrier for biomacromolecules in real samples.

Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis.

BACKGROUND: The deubiquitinase OTUB1 plays critical oncogenic roles and facilitates tumor progression in cancer. However, less is known regarding the aberrant expression, clinical significance and biological functions of the non-coding RNA OTUB1-isoform 2. We aimed to evaluate the OTUB1-isoform 2 levels in gastric cancer and their possible correlation with clinicopathologic features and patient survival to reveal its biological effects in gastric cancer progression. METHODS: Total RNA extraction was performed on 156 gastric cancer case samples, and RT-qPCR was conducted. Chi-square test analysis was used to calculate the correlation between pathological parameters and the OTUB1-isoform 2 mRNA levels. Kaplan-Meier and Cox proportional hazards analyses were used to analyze the overall survival (OS) and disease-free survival (DFS) rates. Nuclear and cytoplasmic RNAs were isolated to detect the subcellular localization of OTUB1-isoform 2. We also assessed whether overexpression of OTUB1-isoform 2 influenced in vitro cell proliferation, cell cycle progression, tumor cell invasion and migration, as well as in vivo nude mouse xenograft and metastasis models. RESULTS: The OTUB1-isoform 2 expression levels were higher in the gastric cancer samples than in the paratumorous gland samples. OTUB1-isoform 2 expression levels tightly correlated with tumor size, lymph node metastasis and TNM staging. Higher OTUB1-isoform 2 expression levels led to significantly poorer OS and DFS rates, and a multivariate analysis revealed that OTUB1-isoform 2 was an independent risk factor for DFS. OTUB1-isoform 2 was predominantly localized in the cell nucleus. Ectopic overexpression of OTUB1-isoform 2 in gastric cancer cells stimulated proliferation by inducing G1-S transition, suppression of cell apoptosis and promotion of tumor cell invasion and migration. Finally, OTUB1-isoform 2 overexpression promoted tumor growth and tumor metastasis in nude mice models. CONCLUSIONS: Our study suggests that OTUB1-isoform 2 independently predicts poor prognosis and promotes tumor progression in gastric cancer. The non-coding RNA OTUB1-isoform 2 should be targeted in future molecular therapies.