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Iron-containing poly(ionic liquid) membranes were prepared by Cu(0)-mediated reversible deactivation radical polymerization, which was achieved to catalyze a heterogeneous Fenton reaction and realize self-cleaning of the membrane surface.

The charged CD-based membrane can precisely discriminate molecules with different charges, molecular weights, or shapes, which was determined by the inner cavities of CDs, outer spaces between CDs, and quaternary ammonium groups of the CD network.

Cationic glycopolymers have attracted great attention as a new type of antibacterial material.

The development of degradable polymeric materials such as degradable polyurethane or polyurea has been much highlighted for resource conservation and environmental protection. Herein, a facile strategy of constructing mechanically strong and tough poly(urea-urethane) (PUU) thermosets that can be degraded under mild conditions by using triple boron-urethane bonds (TBUB) as cross-linkers is demonstrated. By tailoring the molecular weight of the soft segment of the prepolymers, the mechanical performance can be finely controlled. Based on the cross-linking of TBUB units and hydrogen-binding interactions between TBUB linkages, the as-prepared PUU thermosets have excellent mechanical strength of ≈40.2 MPa and toughness of ≈304.9 MJ m

A claw-type Schiff base, tris[N-(2-pyridylmethyl)-2-iminoethyl]amine (Py3Tren), is used as an active ligand for photoinduced atom transfer radical polymerization (Photo-ATRP). CuBr2/Py3Tren was employed as a catalyst for Photo-ATRP of methyl methacrylate (MMA) under the irradiation of ultraviolet or visible light. Well-defined poly(MMA) could be synthesized with high chain-end functionality confirmed by in situ chain extension. Temporal control of Photo-ATRP was successfully demonstrated by switching the light on and off. The polymerization mechanism was finally discussed through UV/vis spectroscopy and electrospray ionization mass spectrometry (ESI-MS) experiments.

Mechanically robust polyurethanes and polyureas with excellent healing and recycling capacities have an extended service life, and can reduce raw material consumption and environmental pollution. In this work, healable, recyclable and mechanically super-strong poly(urea-urethane)s (PUUs) are conveniently fabricated via cross-linking isocyanate-terminated poly(tetramethylene ether glycol) (PTMEG) with nitrogen-coordinated boroxines (NCBs). The tripodal NCBs generate three-dimensionally cross-linked PUUs (denoted as NCB-PUUs) with a high cross-linking density. Meanwhile, hydrogen bonds and phase-separated PTMEG segments can serve as physical cross-linkers to further strengthen NCB-PUUs. As a result, the NCB-PUUs exhibit a tensile strength of ∼47 MPa and a toughness of ∼190 MJ m−3. Because of the high reversibility of NCBs and hydrogen bonds, the NCB-PUUs are capable of efficiently healing and recycling at room temperature with the assistance of ethanol or a water/ethanol mixture to restore their original mechanical strength. NCB-PUUs can be conveniently deposited on solid surfaces by dip-coating and spraying methods to serve as protecting coatings. The NCB-PUU coatings have firm adhesion on solid surfaces and can be doped with organic dyes to display diverse colors. More importantly, the NCB-PUU coatings can heal deep and wide cuts and scratches for multiple times in a given region.

Degradable polymers that play an increasingly important role in the development of sustainable society are highly expected to exhibit not only high mechanical strength, but also superior toughness. Herein, degradable polyurethane thermosets with high mechanical strength and toughness are synthesized by cross-linking isocyanate-terminated prepolymers with boric acids. The incorporation of triple boron–urethane bonds derived from the coupling between hydroxyl groups in boric acids and isocyanate groups in the prepolymers into polyurethanes brings about a significant enhancement in the mechanical properties of the polyurethanes. Typically, PTMEG-HDI-BA1.5 exhibits optimal mechanical performances with an ultimate strength of ∼53.9 MPa, tensile strain of ∼1865%, and toughness of ∼390 MJ m−3. The toughness of poly(boron–urethanes) is even better than that of spider dragline silk (∼180 MJ m−3). The labile nature of the boron–urethanes enables the polyurethane thermosets to be rapidly degraded under mild acid conditions. The PTMEG-HDI-BA1.5 samples can be entirely decomposed in 0.1 M HCl/THF solution in 3 h at room temperature. Meanwhile, the degraded polyurethane thermosets can be further recycled into linear PU oligomers. Based on the above results, a new approach to fabricate degradable polymeric materials with simultaneously high mechanical strength and toughness is provided in this study.

Somatic alterations in cancer genes are being detected in normal and premalignant tissue, placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens. Organoid derivation from dysplastic lesions facilitated genomic, transcriptional, and functional evaluation of gastric premalignancy. Cell cycle regulators, most notably Cdkn2a, were upregulated by p53 inactivation in gastric premalignancy, serving as a barrier to disease progression. Co-deletion of Cdkn2a and Trp53 in dysplastic gastric organoids promoted cancer phenotypes but also induced replication stress, exposing a susceptibility to DNA damage response pathway inhibitors. These findings demonstrate the utility of mouse models that integrate genomic alterations with relevant exposures and highlight the importance of gene-environment interactions in shaping the premalignant state.

It is a long-term pursuit, and also, a challenge to significantly improve the mechanical strength of thermoplastic polymers using readily dispersed polymers as nanofillers. In this study, we demons...

Nondegradable PEGylated protein drugs are known to cause accumulation in the tissue and accelerated blood clearance effect, which inspire people to develop alternative polymers such as polyesters for bioconjugation. However, the hydrophobicity and slow degradation rate of polyesters remain as challenges for typical therapeutic applications. Here, we report the facile synthesis of biodegradable protein–poly(e-caprolactone) conjugates via enzymatic ring opening polymerization (eROP). Candida antarctica lipase B (CALB)–poly(N-hydroxyethyl acrylamide) conjugates with pendent hydroxyl groups were utilized as initiators and catalysts simultaneously for the eROP of e-caprolactone to form amphiphilic graft copolymers. The enzymatic degradation of ester-containing polymers in the conjugates could be significantly accelerated by lipase, leading to total degradation in several days.

Protein-loaded hydrogels were synthesized via biocatalytic atom transfer radical polymerization (ATRP) for the first time. Laccase from Trametes versicolor acted as the ATRPase for the enzymatic polymerizations and was in situ loaded into the porous network of poly(ethylene glycol)-based hydrogels. The use of additional ligands such as tris(2-(dimethylamino)ethyl)amine could significantly increase the polymerization conversion, allowing the polymerizations to occur at ambient or even lower temperature. The rheology and water uptake ratio of hydrogels could be tuned by using different cross-linkers. Immobilized enzymes in the hydrogels have shown decreased yet considerable activity compared with pristine laccase. The hydrogels could be facilely recovered and reused up to six times with no significant decrease in enzyme activity. Such hydrogels were successfully used for the oxidative polymerization of hydroquinone and may find potential applications in protein delivery and water treatment.

The use of a tripodal heptadentate Schiff base, tris[N-(2-pyridylmethyl)-2-iminoethyl]amine (Py3Tren), as an active ligand for atom transfer radical polymerization (ATRP) is reported. The coordination between Py3Tren and CuBr2 in solution is investigated by electrospray ionization mass spectrometry, which reveals the generation of a tripod claw-shaped complex by using equimolar quantities of CuBr2 and Py3Tren. Electrochemical studies of CuBr2/Py3Tren complexes demonstrate more negative redox potentials and higher activities compared with those of bidentate CuBr2/N-ethyl-2-pyridylmethanimine (PyEthyl) complexes. Subsequently, CuBr/Py3Tren is employed as a catalyst for the normal ATRP of methyl methacrylate (MMA). Well-defined poly(MMA) with controlled molecular weight and narrow polydispersity could be synthesized with high conversions and fast rates even at ambient temperature (30 °C). Activators regenerated by electron transfer (ARGET) ATRP and supplemental activators and reducing agents (SARA) ATRP of acrylate monomers using Py3Tren as the ligand are also performed to reduce the amounts of metal catalysts for polymerizations.

A facile synthetic route is reported toward sugar-containing pyridinium-based poly(ionic liquid)s (PILs). Reversible deactivation radical polymerization of 4-vinyl pyridine could generate a well-defined poly(4-vinyl pyridine) in a self-generating biphasic system. Subsequent quaternization and anion exchange reaction could yield a library of functional PILs with pendent sugar units and varied anions.

Polymerization-induced self-assembly (PISA) has evolved as a facile pathway for the in situ formation of polymeric nanomaterials with unique morphologies. However, aqueous PISA by atom transfer radical polymerization (ATRP) for the generation of protein-based nanoassemblies is still challenging. In this research, Candida antarctica lipase B (CALB) is modified as the macroinitiator for Cu(0)-mediated reversible deactivation radical polymerization (Cu(0)-RDRP) of both hydrophilic and hydrophobic monomers in water or water/methanol mixtures. Different acrylamides and acrylates are successfully polymerized in the presence of lipase-based macroinitiators under mild reaction conditions and it is found that the lipase-catalyzed hydrolysis of ester bonds from poly(acrylates) is very significant. The PISA of lipase–hydrophobic polymer conjugates could directly generate spherical nanoparticles in aqueous solution without further processing. Activity tests further demonstrate preservation or even a significant increase of the enzymatic activity for the conjugates, indicating the potential application of aqueous PISA in protein delivery and enzyme immobilization.

Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics of these alterations are poorly understood. Here we study chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) by multi-regional whole-genome sequencing analysis of BE samples with dysplasia and microscopic EAC foci. Through haplotype-specific copy-number analysis of BE genome evolution, we identified distinct patterns of episodic copy-number evolution consistent with the outcomes of abnormal mitosis and dicentric chromosome breakage. While abnormal mitosis, including whole-genome duplication, accounts for most chromosome or arm-level copy-number changes, segmental copy-number alterations display signatures of multi-generational evolution of unstable dicentric chromosomes. Continuous evolution of dicentric chromosomes through breakage-fusion-bridge cycles and chromothripsis rapidly increases genomic complexity and diversity among BE cells, culminating in the generation of distinct focal amplifications. These mutational processes enable multiple subclones within small dysplastic areas to undergo parallel transformation to cancer following acquisition of distinct oncogenic amplifications. Our results demonstrate how chromosomal instability drives clonal diversification in precancer evolution and promotes tumorigenesis in primary human samples.

Supramolecular assemblies with reversible boronate ester linkages are facilely prepared via self-assembly between cyclodextrin-centered glycoclusters and 4,4'-(1,2-diphenylethene-1,2-diyl)bis(1,4-phenylene)diboronic acid (TPEDB). Such sphere-like assemblies have shown a typical aggregation-induced emission (AIE) effect and could act as fluorescent probes for the sensitive detection of phenols in water.

Covalent coupling of hydrophobic polymers to the exterior of hydrophilic proteins would mediate unique macroscopic assembly of bioconjugates to generate amphiphilic superstructures as novel nanoreactors or biocompatible drug delivery systems. The main objective of this study was to develop a novel strategy for the synthesis of protein-polymer giant amphiphiles by the combination of copper-mediated living radical polymerization and azide-alkyne cycloaddition reaction (CuAAC). Azide-functionalized succinimidyl ester was first synthesized for the facile introduction of azide groups to proteins such as albumin from bovine serum (BSA) and laccase from Trametes versicolor. Alkyne-terminal polymers with varied hydrophobicity were synthesized by using commercial copper wire as the activators from a trimethylsilyl protected alkyne-functionalized initiator in DMSO under ambient temperature. The conjugation of alkyne-functionalized polymers to the azide-functionalized laccase could be conducted even without additional copper catalyst, which indicated a successful self-catalyzed CuAAC reaction. The synthesized amphiphiles were found to aggregate into spherical nanoparticles in water and showed strong relevance to the hydrophobicity of coupled polymers. The giant amphiphiles showed decreased enzyme activity yet better stability during storage after chemical modification and self-assembly. These findings will deepen our understanding on protein folding, macroscopic self-assembly, and support potential applications in bionanoreactor, enzyme immobilization, and water purification.

It is challenging to regenerate enzyme carriers when covalently immobilized enzymes suffered from inactivation during continuous operations. Hence, it is urgent to develop a facile strategy to immobilize enzymes reversibly. Herein, the non-covalent interaction between protein and carbohydrate was used to adsorb and desorb enzymes reversibly. Laccase was immobilized onto glycopolymer microspheres via protein-carbohydrate interaction using lectins as the intermediates. The enzyme loading and immobilization yield were up to 49 mg/g and 77.1% with highly expressed activity of 107.9 U/mg. The immobilized laccase exhibited enhanced pH stability and high activity in catalyzing the biodegradation of paracetamol. During ten successive recoveries, the immobilized laccases could be recycled while maintaining relatively high enzyme activity. The glycopolymer microspheres could be efficiently regenerated by elution with an aqueous solution of mannose or acid for further enzyme immobilization. This glycopolymer microspheres has excellent potential to act as reusable carriers for the non-covalent immobilization of different enzymes.

Excess boron in water could result in a critical hazard to plants and humans. Traditional treatment approaches cannot efficiently remove boron from water, especially during seawater desalination using reverse osmosis technology. Achieving satisfactory adsorption capacity and rate for boron remains an unmet goal for decades. Herein, we report cellulose-derived polyols as high-performance adsorbents that can rapidly remove boron and organic pollutants from water. Cellulose-derived polyols were synthesized from saccharides and cellulose via controlled radical polymerization and click reaction. Remarkably, CA@NMDG can adsorb boron with an astonishing capacity of ~34 mg g-1 in 10 min, which surpasses all those cellulose-based materials reported thus far, meanwhile, much faster than those of commercial adsorption resin. Moreover, cellulose-derived polyols also showed high removal efficiencies (70–98% in several minutes) toward certain organic pollutants, including Congo red and Reactive Blue 19. The water-insoluble characteristic of cellulose-derived polyols is advantageous to be separated from the treated sewage after adsorption for reuse. This work provides a novel insight into the fabrication of safe, fast, and high-capacity cellulose adsorbents for water purification.

Metastasis is a core hallmark of cancer that leads to high mortality of cancer patients, especially in hepatocellular carcinoma (HCC). However, the underlying mechanisms of long noncoding RNAs (lncRNAs) in HCC metastasis remain largely unknown. We found that ID2-AS1 expression decreased in metastatic HCC cell lines and HCC tissues, and lower ID2-AS1 expression predicted reduced overall survival in HCC patients. ID2-AS1 significantly suppressed the migration, invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ID2-AS1 regulated the transcription of its adjacent gene inhibitor of DNA binding 2 (ID2) by blocking the binding of histone deacetylase 8 (HDAC8) on the ID2 enhancer. Furthermore, ID2-AS1 and ID2 suppressed the Twist-induced epithelial-mesenchymal transition (EMT) in HCC cells. In addition, ID2 expression was also significantly decreased in HCC tissues and was positively correlated with ID2-AS1 in HCC tissues and HCC cell lines. Taken together, our findings demonstrated that ID2-AS1 regulated adjacent ID2 transcription by manipulating chromatin modification and that the newly identified ID2-AS1/ID2 axis suppressed HCC metastasis by regulating EMT processes. Our findings provide insights into the molecular mechanisms underlying the metastasis of HCC cells.

Novel self-cleaning catalytic membranes are prepared for water treatment via an integration of heterogeneous Fenton and membrane process. Polysulfone (PSF) based functional copolymers with pendant ferrocene groups are facilely synthesized via a combination of controlled radical polymerization and ester coupling reaction. Different catalytic membranes with tuned surface hydrophilicity are then prepared through non-solvent phase inversion method based on functional ferrocene- and hydroxyl-containing PSF. These membranes have demonstrated high activity in catalyzing Fenton-type reactions, which also lead to outstanding antifouling performance for the membrane. Finally, the catalytic membranes are successfully used for treatment of waste water containing different dyes. The proposed strategy in this work may provide worthy guidance to catalytic membranes, which is promising for water purification through simultaneous Fenton reaction and membrane separation.

It remains a challenge to fabricate sacrificial films that are stable in most of solvents and can be readily decomposed on demand. Here we report the fabrication of a near-infrared (NIR) light decomposable sacrificial film by layer-by-layer (LbL) assembly of UV-light-decomposable poly((4-(2-bromoethoxy)-5-methoxy-2-nitrobenzyl acrylate) triethylammonium bromide) (PNBA-TEA), poly(sodium 4-styrene-sulfonate) (PSS), branched polyethyleimine (bPEI), and lanthanide-doped upconversion nanoparticles (UCNPs). The [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films are stable in deposition solutions of various materials and decompose upon NIR light irradiation. In the [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films, UCNPs can convert NIR light into UV light, which can decompose PNBA-TEA. After immersing the NIR light-irradiated [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films in 0.1 M aqueous NaHCO3 solution, the disintegration of the entire films occurs because of the repulsive force between the negatively charged photoproduct of PNBA-TEA and PSS. LbL-assembled (PAH/PAA)*50 films deposited on top of the NIR-light-decomposable [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films can be conveniently released to produce large-area and defect-free (PAH/PAA)*50 free-standing films after NIR light irradiation and subsequent immersion in 0.1 M aqueous NaHCO3 solution. Because of the satisfactory stability and on-demand decomposable property, the [(PNBA-TEA/PSS)*2/(bPEI/UCNPs)*3]*2 films are promising as sacrificial layers for the fabrication of various free-standing films.

The fabrication of mechanically robust polymeric materials capable of self-healing and recycling remains challenging because the mobility of polymer chains in such polymers is very limited. In this work, mechanically robust supramolecular thermosets capable of healing physical damages and recycling under mild conditions are fabricated by trimerization of bi-( ortho-aminomethyl-phenylboronic acid)- and tri-( ortho-aminomethyl-phenylboronic acid)-terminated poly(propylene glycol) oligomers (denoted as Bi-PBA-PPG and Tri-PBA-PPG, respectively). The resultant supramolecular thermosets are cross-linked by dynamic covalent bonds of nitrogen-coordinated boroxines. The mechanical properties of the supramolecular thermosets can be systematically tailored by varying the ratios between Tri-PBA-PPG and Bi-PBA-PPG, which changes the cross-linking density of nitrogen-coordinated boroxines and the topology of the supramolecular thermosets. The mechanically strongest supramolecular thermosets with a molar ratio of Tri-PBA-PPG to Bi-PBA-PPG being 1:2 have a glass transition temperature of ∼36 °C, a tensile strength of ∼31.96 MPa, and a Young's modulus of ∼298.5 MPa. The high reversibility of nitrogen-coordinated boroxines and the flexibility of poly(propylene glycol) chains enable the supramolecular thermosets with the strongest mechanical strength to be highly efficiently healed at 55 °C and recycled under a pressure of 4 MPa at 60 °C to regain their original mechanical strength and integrity.

Nuclear factor‐κB (NF‐κB) activation is one of the major mediators of inflammation‐induced cancer cell growth and progression. In previous studies, we screened a series of microRNAs (miRNAs) that targeted the NF‐κB signaling pathway. In this study, we showed that miR‐127‐5p suppressed NF‐κB activity through inhibition of p65 nuclear translocation. In addition, miR‐127‐5p also inhibited the transcription of downstream targets of the NF‐κB signaling pathway. While exploring the mechanism of the inhibition of NF‐κB activity by miR‐127‐5p, we found that miR‐127‐5p decreased the phosphorylation of p65. MicroRNA‐127‐5p inhibited the growth and colony formation of hepatocellular carcinoma (HCC) cells and decreased biliverdin reductase B (BLVRB) expression by directly binding to its 3′‐UTR. RNA interference of BLVRB suppressed HCC cell growth, whereas the overexpression of BLVRB promoted HCC cell growth. Furthermore, BLVRB blockade inhibited the phosphorylation of p65 protein and the expression of downstream targets of the NF‐κB signaling pathway, mimicking the function of miR‐127‐5p. The restoration of BLVRB in HCC cells overexpressing miR‐127‐5p impaired the suppression of HCC growth by miR‐127‐5p. Moreover, miR‐127‐5p was downregulated in 58% of HCC samples. In summary, we found that miR‐127‐5p suppressed NF‐κB activity by directly targeting BLVRB in HCC cells, and this finding improves our understanding of the molecular mechanism of inflammation‐induced HCC growth and proliferation and the successful inhibition of NF‐κB activity by cancer treatment.

Metastasis is one of the causes of cancer death. Functions and mechanisms of microRNAs (miRNAs) involved in hepatocellular carcinoma (HCC) metastasis are largely unknown. Here, a miRNA microarray analysis was performed in MHCC-97L, MHCC-97H and HCC-LM3 cells with gradually increasing metastatic potential to disclose crucial miRNAs involved in HCC metastasis. miR-192 expression decreased and negatively correlated with vascular invasion in HCC specimens. Gain and loss of function studies revealed that miR-192 significantly suppressed metastasis of HCC cells in vitro and in vivo. Solute carrier family 39 member 6 (SLC39A6) was identified as a direct and functional target of miR-192. In addition, SLC39A6 negatively correlated with miR-192 in HCC samples and promoted HCC cell migration and invasion. Moreover, miR-192 decreased SLC39A6 expression, subsequently downregulating SNAIL and upregulating E-cadherin expression. Suppression of migration and invasion caused by miR-192 overexpression was alleviated by exogenous Snail expression. Intriguingly, lower miR-192 expression and higher SLC39A6 expression significantly contributed to poorer outcomes in HCC patients. Multivariate analysis indicated that miR-192 was an independent and significant predictor of HCC patient overall survival. In conclusion, we newly determined that miR-192 targeted the SLC39A6/SNAIL pathway to reduce tumor metastasis in HCC cells. This axis provided insights into the mechanism underlying miRNA regulation of HCC metastasis and a novel therapeutic target for HCC treatment.

Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis

// Yan Li 1,* , Dan Xu 1,* , Chunyang Bao 1,* , Yuannv Zhang 1 , Di Chen 1 , Fangyu Zhao 1 , Jie Ding 2 , Linhui Liang 2 , Qifeng Wang 2 , Li Liu 2 , Jinjun Li 1 , Ming Yao 1 , Shenglin Huang 2 and Xianghuo He 1,2 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China * These authors contributed equally to this work Correspondence: Xianghuo He, email: // Shenglin Huang, email: // Keywords : MicroRNA-135b; RECK; EVI5; HSF1; Hepatocellular Carcinoma Received : September 24, 2014 Accepted : December 10, 2014 Published : December 11, 2014 Abstract MicroRNAs (miRNAs) often localize to chromosomal fragile sites and are associated with cancer. In this study, we screened for the aberrant and functional miRNAs in the regions of copy number alterations (CNAs) in hepatocellular carcinoma (HCC), and found that miR-135b was frequently amplified and upregulated in HCC tissues. The expression level of miR-135b was inversely correlated with the occurrence of tumor capsules. In addition, miR-135b promoted HCC cell migration and invasion in vitro and metastasis in vivo . The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the direct and functional targets of miR-135b in HCC. Furthermore, we observed that heat shock transcription factor 1 (HSF1) directly activated miR-135b expression, consequently enhancing HCC cell motility and invasiveness. The newly identified HSF1/miR-135b/RECK&EVI5 axis provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.

Circular RNAs (circRNAs) comprise a novel class of widespread non-coding RNAs that may regulate gene expression in eukaryotes. However, the characterization and function of circRNAs in human cancer remain elusive. Here we identified at least 5500 distinct circRNA candidates and a series of circRNAs that are differentially expressed in gastric cancer (GC) tissues compared with matched normal tissues. We further characterized one circRNA derived from the PVT1 gene and termed it as circPVT1. The expression of circPVT1 is often upregulated in GC tissues due to the amplification of its genomic locus. circPVT1 may promote cell proliferation by acting as a sponge for members of the miR-125 family. The level of circPVT1 was observed as an independent prognostic marker for overall survival and disease-free survival of patients with GC. Our findings suggest that circPVT1 is a novel proliferative factor and prognostic marker in GC.

Circular RNAs (circRNAs) represent a novel class of widespread non-coding RNAs in eukaryotes. They are unusually stable RNA molecules with cell type-specific expression patterns, and are predominantly present in the cytoplasm. We recently demonstrated the existence of abundant circRNAs in exosomes and suggest a potential application of exosomal circRNAs for cancer detection.

Constitutive activation of the proinflammatory transcription factor nuclear factor κB (NF-κB) plays an important role in progression of hepatocellular carcinoma (HCC). Emerging modulators of NF-κB signaling are noncoding RNAs, especially microRNAs (miRNAs). We previously identified miRNAs that reduced the induction of NF-κB activity upon addition of tumor necrosis factor-α (TNFα) to HCC cells. We found that among these miRNAs, the abundance of liver-enriched miR-194 was decreased in HCC tissue and that low abundance of miR-194 correlated with a high occurrence of vascular invasion. Overexpressing miR-194 suppressed HCC cell migration and invasiveness in culture and metastatic seeding in mice. Transcripts encoding tripartite motif containing 23 (TRIM23), a ubiquitin ligase involved in NF-κB activation, and chromosome 21 open reading frame 91 (C21ORF91), a protein of unknown function, were identified as direct targets of miR-194 in HCC cells; knocking down either protein decreased the activity of a luciferase NF-κB reporter. Furthermore, the NF-κB pathway activator TNFα, an inflammatory cytokine, inhibited the transcription of miR-194 by decreasing the abundance of hepatocyte nuclear factor-1α (HNF-1α). The abundance of miR-194 positively correlated with that of HNF-1α and inversely correlated with that of TNFα in human HCC tissue. Thus, we identified a pathway in which TNFα-NF-κB signaling switches off negative regulation by suppressing HNF-1α-mediated expression of miR-194, revealing insight into the mechanisms linking inflammatory pathways, miRNA, and HCC metastasis.